This document discusses transdermal therapeutic systems (TTS). It begins by defining TTS as self-contained dosage forms that deliver drugs through intact skin at a controlled rate. It then covers various topics related to TTS including advantages/disadvantages, factors affecting skin permeation, mechanisms of drug permeation, and techniques to enhance permeation like physical methods (iontophoresis, electroporation, etc.), chemical enhancers, and patch design/evaluation. The document provides details on the design, preparation, and evaluation of various TTS with the goal of improving transdermal drug delivery.

1. TRANSDERMAL THERAPEUTIC
SYSTEMS
BY
NADIKATLAANUSHA
M.Pharm

2. CONTENTS
 INTRODUCTION
 ADVANTAGES & DISADVANTAGES OF TDDS
 FACTORS AFFECTING PERCUTANEOUS ABSORPTION
 SKIN BARRIER, SKIN PERMEATION PATHWAYS
 MECHANISM OF DRUG PERMEATION
 FACTORS AFFECTING TRANSDERMAL PERMEABILITY
 TRANSDERMALABSORPTION ENHANCERS
 PHYSICAL TECHNIQUES
• Iontophoresis
• Electroporation
• Ultrasounds (sonophoresis, phonophoresis)
• Microneedles
• Thermal poration
• Radio frequency
• Jet propelled particulate delivery
• Super saturation
• Photomechanical waves
 CHEMICAL ENHANCERS & COMBINATORIAL ENHANCEMENT TECHNIQUES FOR
TRANSDERMAL DELIVERY
 THE MECHANISMS OF ENHANCEMENT OF TRANSDERMAL DRUG DELIVERY
SYSTEMS ANUSHA NADIKATLA

3. CONTENTS
 DESIGN OF TRANSDERMAL PATCHES
• Polymers
• Active ingredient
• Permeation enhancers
• Pressure
• Sensitive adhesive
• Backing laminate
• Release liner
 PREPARATION OF DIFFERENT TYPES OF TRANSDERMAL PATCHES
• Membrane permeation controlled systems
• Adhesive dispersion type systems
• Matrix diffusion controlled systems
• Micro reservoir type dissolution controlled systems
 EVALUATION OF TRANSDERMAL THERAPEUTIC SYSTEMS
 GENERAL CLINICAL CONSIDERATIONS IN THE USE OF TDDS
 APPLICATIONS OF TRANSDERMAL THERAPEUTIC SYSTEMS
 FUTURE PROSPECTS
 CONCLUSION
 REFERENCES ANUSHA NADIKATLA

4. INTRODUCTION
DEFINITION
Transdermal drug delivery systems (TDDS) can be defined as self-
contained discrete dosage forms which, when applied to the intact
skin, delivers the drug(s) through the skin at a controlled rate to the
systemic circulation.
 Development of transdermal delivery system started in 1970s, and in
1979, the first transdermal patch of scopolamine was approved by
USFDA for the treatment of motion sickness and later on
nitroglycerine patch was marketed for the management of angina
pectoris.
 Henceforth, numbers of drugs viz. clonidine, nitroglycerine, fentanyl,
oxybutonin, scopolamine, lidocaine and testosterone have been
successfully delivered through transdermal route.
 For transdermal drug delivery, it is considered ideal if the drug
penetrates through the skin to the underlying blood supply without
drug buildup in the dermal layers.
ANUSHA NADIKATLA

5. ANUSHA NADIKATLA

6. ADVANTAGES OF TDDS
 They provide extended therapy with a single application, thereby
improving patient compliance over other dosage forms requiring more
frequent dose administration.
 It reduces the typical dosing schedule to once daily or even once
weekly.
 Its non-invasive characteristics, helps in improving patient
compliance.
 The activity of drugs having short half-lives is extended through the
reservoir of drug present in the therapeutic delivery system and its
controlled release characteristics.
 By avoiding hepatic first pass metabolism, there by possibly avoiding
the drug’s deactivation by digestive and liver enzymes.
 It provides constant blood level in the plasma for drugs with narrow
therapeutics index, thus achieving improved bioavailability.
ANUSHA NADIKATLA

7.  They can avoid gastrointestinal drug absorption difficulties caused by
gastrointestinal pH, enzymatic activity and drug interactions with
food, drink, or other orally administered drugs.
 They can substitute for oral administration of medication when that
route is unsuitable, as in instances of vomiting and/or diarrhea.
 It is suitable for unconscious patients.
 Improves patient compliance due to simpler, pain free delivery,
potential for home administration.
 Drug therapy may be terminated rapidly by removal of the application
from the surface of the skin.
 Ease of rapid identification of the medication in emergencies (e.g.,
nonresponsive, unconscious, or comatose patient) due to the physical
presence, features and identifying-markings on the TDDS.
ANUSHA NADIKATLA

8. DISADVANTAGES OF TDDS
 Only relatively potent drugs are suitable candidates for transdermal
delivery due to the natural limits of drug entry imposed by the skin’s
impermeability.
 Not suitable for irritating drugs.
 Some patients may develop contact dermatitis at the site of application
due to one or more of the system components, necessitating
discontinuation.
 Poor diffusion of large molecules.
 Limited dose is required.
 Cannot deliver ionic drugs.
 Cannot achieve high concentrations of drug in blood.
 Cannot deliver drug in pulsatile manner.
ANUSHA NADIKATLA

9. FACTORS AFFECTING PERCUTANEOUS ABSORPTION
• Drug concentration is an important factor.
• Larger the area of application, more the drug is absorbed.
• The aqueous solubility of a drug determines the concentration
presented to the absorption site, and the partition coefficient
influences the rate of transport across the absorption site.
• Drugs generally penetrate the skin better in their un-ionized form.
• Nonpolar drugs tend to across the cell barrier through the lipid-rich
regions, whereas the polar drugs favor transport between cells.
• Hydration of the skin generally favors percutaneous absorption. The
TDDS acts as an occlusive moisture barrier through which sweat
cannot pass, increasing skin hydration.
• Percutaneous absorption appears to be greater when the TDDS is
applied to a site with a thin horny layer than with a thick one.
• Generally, the longer the medicated application is permitted to remain
in contact with the skin, the greater is the total drug absorption.
ANUSHA NADIKATLA

10. SKIN BARRIER
• Skin provides enormous surface area (approx 2 m2) for absorption
with minimal proteolytic activity.
• It is composed of three layers:
1. Epidermis
2. Dermis
3. Subcutaneous tissue
• Skin is flexible enough to resist permanent distortion from movement
and thin enough to allow stimulation.
• The main barrier for the transdermal delivery is slow diffusion
through stratum corneum (SC), which is known to be a dead layer.
• It is documented that polar molecules mainly permeate through the
polar pathway within the hydrated stratum corneum, while non-polar
molecules through the lipid matrix of the stratum corneum.
ANUSHA NADIKATLA

11. ANUSHA NADIKATLA

12. EPIDERMIS
Epidermis is the outermost layer of skin, composed of stratified epithelium
cells. It is composed of 2 layers
i. Stratum corneum
ii. Stratum germinativum
i. Stratum corneum: It is the outermost layer of epidermis. It consists of
flattened, dehydrated, keratinised cells.
ii. Stratum germinativum: It is regenerative layer of epidermis. It contains
basal cells which multiply and undergo slow upword migration. This process of
regeneration of the stratum corneum is made up of 3 layers of stratum
germinativum
a. Stratum spinosm (prickly layer)
b. Stratum granulosm (granular layer)
c. Stratum lucidum (clear or basal layer)
TISSUE WATER CONTENT FUNCTION
Stratum Corneum 20 % To maintain flexibility & softness.
Stratum Germinativum 70% Regenerates new Stratum corneum.
ANUSHA NADIKATLA

13. SKIN PERMEATION PATHWAYS
The physiology of skin illustrates the three feasible pathway exist for
passive transport of active through the skin.
(A) Diffusion through hair follicles and sweat ducts,
(B) Trans-cellular diffusion through both the keratinocytes and lipid lamellae,
(C) Intercellular diffusion through the lipid and protein in series.
ANUSHA NADIKATLA

14. MECHANISM OF DRUG PERMEATION
Sorption of a parenteral molecule on to the
surface layers of stratum corneum.
Diffusion through it & viable epidermis &
finally at the papillary layers of dermis.
The molecule is taken up into the
microcirculation for subsequent systemic
distribution.
The viable tissue layers & the capillaries are relatively permeable & the
peripheral circulation is sufficiently rapid so that for the great majority of
penetrant, diffusion through the stratum corneum is often the rate limiting
step.
ANUSHA NADIKATLA

15. ANUSHA NADIKATLA

16. FACTORS AFFECTING TRANSDERMAL PERMEABILITY
PHYSICOCHEMICAL
PROPERTIES OF PARENT
MOLECULE:
Solubility and partition co- efficient
pH condition
Penetrant concentration
PHYSICOCHEMICAL
PROPERTIES OF DRUG DELIVERY
SYSTEM :
Release characteristic
Composition of drug delivery system
Permeation enhancer used
PHYSIOLOGICALAND
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
ANUSHA NADIKATLA

17. PHYSICOCHEMICAL PROPERTIES OF PARENT MOLECULE
a) Solubility and partition co- efficient:
• Solubility of a drug influences its ability to penetrate the 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.
b) pH & penetration concentration:
• Moderate pH is favorable because if solutions with high or low pH
will result in destruction to the skin. e.g. In case of ephedrine and
scopolamine, the transdermal flux of the drug increases with
increasing pH up to approximately 1.2 higher than their
• Higher the concentration of the drug in vehicle faster the absorption.
ANUSHA NADIKATLA

18. PHYSICOCHEMICAL PROPERTIES OF DRUG DELIVERY
SYSTEM
a) Release characteristic: Solubility of drug in vehicle affect on the release
rate.
b) Composition of drug delivery system: It not only effects the rate of drug
release but also the permeability through STC.
Example: methyl salicylate is more lipophilic than its parent acid (Salicylic
acid). When applied to skin from fatty vehicle methylsalicylate yielded higher
absorption.
BIOLOGICAL FACTORS
a) Skin age:
Skin of foetus, young ones and elders is more permeable than adult tissue.
b) Thickness of stratum corneum:
e.g. Absorption is low from region as foot and palm
c) 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. ANUSHA NADIKATLA

19. PHYSIOLOGICALAND PATHOLOGICAL CONDITION OF
SKIN
a) Lipid film: It acts as protective layer to prevent removal of moisture
from skin. Deffating of this film will decrease TD absorption.
b) 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.
c) Skin temperature: Skin temperature increases absorption of drugs
also increase. Ex: aspirin-51°C
d) 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.
e) Pathological injury to skin: Cut inflammation, rashes, mild burn
where promote the absorption.
ANUSHA NADIKATLA

20. TRANSDERMAL ABSORPTION ENHANCERS
PHYSICAL TECHNIQUES
IONTOPHORESIS
ELECTROPORATION
ULTRASOUND
MICRONEEDLES
THERMAL PORATION
RADIO FREQUENCY
JET PROPELLED PARTICULATE DELIVERY
SUPER SATURATION
PHOTOMECHANICAL WAVES
CHEMICAL
ENHANCERS
COMBINATORIAL
ENHANCEMENT
TECHNIQUES
ANUSHA NADIKATLA

21. PHYSICAL TECHNIQUES
IONTOPHORESIS
• Iontophoresis is delivery of a charged chemical compound across the
skin membrane using an electrical field.
• It involves the use of small electric current usually 0.5 A/cm2 to a
drug reservoir on the surface of the skin to facilitate the transfer of
drug across the skin.
• In this technique two electrolyte chamber containing electrode are
placed on the skin surface and driven by a constant current source.
• This technique ensures the delivery of drug in controlled manner
because the amount of compound delivered is directly proportional to
the quantity of charge passed.
ANUSHA NADIKATLA

22. Basic design of iontophoretic delivery devices
Drug is placed on the skin under the active electrode, and a current (< 0.5
mA) passed between the two electrodes effectively repelling drug away
from the active electrode and into the skin. ANUSHA NADIKATLA

23. • The mechanism of enhancement by iontophoresis could be the
electrophoresis (i.e. migration of molecule with a net charge under the
influence of an electric field) secondly increased skin permeability and
electro osmosis (i.e. movement in an electric field of liquid within a
porousmedium having a fixed net charge).
• Advantage: The potential for dosing accuracy and thus pulsatile delivery
profile and avoidance of side effects as a result of controlled drug input.
• Adverse effect: Local erythema at the site of application.
• Iontophoresis-enhanced transdermal delivery has shown some promise
on micro as well as macro molecules, peptide and protein
administration.
• Iontophoresis has been investigated for treatment of various disease
conditions viz cardiovascular disease, diabetes, osteoporosis and paget’s
disease, pain management, inflammation, parkinson’s and alzheimer’s
disease, migraine, psoriasis, skin cancer, emesis, virus infectious disease.
• A number of drugs have been the subject of iontophoretic studies, they
include lidocaine, dexamethasone, amino acids, peptides, insulin,
verapamil, propranolol etc. ANUSHA NADIKATLA

24. MARKETED PRODUCTS BASED ON IONTOPHORESIS
TECHNOLOGY
• E-Trans: Developed by Alza it is an iontophoretic drug delivery
based system used to deliver drug both locally and systemically by
using low level electrical energy.
• Phores or PM 850 and 900: Developed by IOMED Inc., is used to
administer soluble salts and other drugs into the body for medical
purposes as an alternative to hypodermic injection to avoid any
damage caused by needle insertion when the target tissue is
traumatized.
• WEDD: Wearable electronic disposable drug delivery (WEDD)
developed by BirchPoint Medical Inc. is a portable, disposable patch
having a thin, flexible battery having capability to supply variable
voltages for versatility in drug delivery and expands the range of
drugs which can be delivered by iontophoresis
ANUSHA NADIKATLA

25. ELECTROPORATION
• Electroporation involves the use of large trans-membrane voltages
caused by electric pulses (10μs–100ms) which create reversible pores
in the membrane.
• Electroporation has been widely used in cell biology for different
purposes: gene transfer in mammalian cells, and introducing RNA,
proteins, dyes, nucleotide and antibodies into cells.
• Electroporation has been explored as a potential transdermal drug
delivery technique to compromise the obstacle function of the stratum
corneum.
• The investigators observed diminished resistance of the skin by three
orders of magnitude during electroporation within microseconds.
• The flux of active substance also reported to increase up to 10–104
fold for neutral and highly charge molecules.
ANUSHA NADIKATLA

26. Examples:
• Delivery of physostigmine for organophosphate poisoning.
• Electrochemotherapy, to increase the bioavailability of cytotoxic drug
into tumor cells by applying high voltage pulses.
• Investigating feasibility of transdermal electroporation for insulin-
loaded nanocarriers. It was observed that electroporation of
nanoparticles resulted in fourfold enhancement in insulin deposition in
rat skin. Finally it was concluded that electroporation of polymeric
nanosystems can be successfully used as alternative to injectable
administration for the delivery of insulin loaded nanocarriers.
ANUSHA NADIKATLA

27. BASIC DESIGN OF ELECTROPORATION BASED DELIVERY
DEVICES
Drug is placed on the skin beneath the electroporation probe. Short
pulses of high voltage current are passed through the probe and drug
molecules are hypothesized to move into the skin through a combination
of pore formation and electrical repulsion.
ANUSHA NADIKATLA

28. ULTRASOUNDS
(SONOPHORESIS, PHONOPHORESIS)
• The application of ultrasound of a suitable frequency significantly
enhances the transdermal transport of drugs-a phenomenon referred to as
phonophoresis or sonophoresis.
• Sonophoresis occurs because ultrasound waves stimulate micro-
vibrations within the skin epidermis and increase the overall kinetic
energy of molecules making up topical agents.
• It is thought that high-frequency ultrasound can influence the integrity of
the stratum corneum and thus affect its penetrability.
• Applications of ultrasounds to skin make some defects in the skin and
those defects facilitate the delivery of active medicaments via stratum
corneum.
ANUSHA NADIKATLA

29. BASIC DESIGN OF SONOPHORETIC DELIVERY DEVICES
Sonophoresis employs ultrasound waves
ranging from 20 kHz to 10 MHz with
intensities of up to 3W cm-2 have been
applied to mitigate the stratum corneum
barrier property. Drug is placed on the
skin beneath the ultrasonic probe.
Ultrasound pulses are passed through the
probe and drug molecules are
hypothesized to move into the skin
through a combination of physical wave
pressure and permeabilisation of
intercellular bilayers. The formation of
bubbles in the intercellular lipid space
caused by cavitation increases bilayer
fluidization and resultant permeability.
Transdermal transport enhancement using
lowfrequency ultrasound (f < 100 kHz)
has been found to be more effective than
high frequency ultrasound. The
enhancement induced by low-frequency
ultrasound is up to 1000-fold higher than
that induced by therapeutic ultrasound.
ANUSHA NADIKATLA

30. Several phenomena may occur in the skin upon ultrasound exposure
these include:
(i) cavitation (generation and oscillation of gas bubbles),
(ii) thermal effects (temperature increase),
(iii) induction of convective transport,
(iv) mechanical effects (occurrence of stresses due to pressure variation
induced by ultrasound).
Examples:
 Application of ultrasound enhances the transdermal transport of both,
biomolecules and drugs alike.
 This technology is helpful in macromolecular drug delivery in
noninvasive glucose monitoring in patients with diabetes and
acceleration of topical anaesthetic activation.
 Sonophoresis has been shown to increase skin permeability to various
low and high molecular weight drugs, including insulin and heparin.
 SonoPrep is an ultrasound device developed by Sontra (Massachusetts)
which had helped deliver interferon,erythropoietin, mannitol and insulin.
ANUSHA NADIKATLA

31. MICRONEEDLES
Microneedles are recently used techniques for transdermal drug delivery,
designed to form a physical pathway through the upper epidermis to
enhance skin permeability. In this technology needles of micron dimension
are inserted into skin surface to create the holes that facilitate the drug
transport. Clinical trials have already shown that microneedles are painless
and hence well tolerated by subjects when inserted into the human skin.
Examples:
• The first study was carried out by Henry et al to determine the feasibility
of microneedles to increase transdermal delivery of calcein.
• Later, Martanto et al delivered insulin to diabetic hairless rats in vivo to
determine the fall in blood glucose level by insulin in diabetic animal
using microneedles.
• In another study 70% drop in blood glucose level over a 5-h period after
the insulin administration was observed when single glass microneedles
fabricated using a micropipette puller and beveler with a tip radius of 60
μm were inserted into the skin of diabetic hairless rats in vivo.
ANUSHA NADIKATLA

32. THE BASIC DESIGN OF MICRONEEDLE DELIVERY DEVICES
Needles are placed onto the skin surface so that they penetrate the
stratum corneum and epidermis without reaching the nerve endings
present in the upper dermis.
ANUSHA NADIKATLA

33. THERMAL PORATION
• Heat is applied to the skin that creates pores in the stratum corneum,
thereby increasing skin permeability.
• This technique has been utilized for the transport of DNA vaccines and
conventional drugs to animal. Shorter exposure (< 1 s) to higher
temperatures (>100˚C) can dramatically increase skin permeability.
• Higher temperatures increase microcirculation and blood vessel
permeability, thus facilitating drug transfer to the systemic circulation.
• Drug solubility, both in the patch formulation and within the skin, may
increase with a rise in temperature.
• Most importantly, because the addition of heat slightly compromises the
barrier function of the skin, patients should not apply any external heat
source to a traditional transdermal patch without first consulting their
physician.
Example: The first patch to utilize this technology, S-Caine, is a topical
anesthetic patch resembling Lidoderm® and EMLA® that is intended to
deliver a proprietary combination of lidocaine and tetracaine locally.
ANUSHA NADIKATLA

34. RADIO FREQUENCY
• Radiofrequency (RF) driven micro channeling is a new method of
transdermal drug delivery. In this technique arrays of around 100
microelectrodes per square cm are placed over the skin surface to
produce radiofrequencies which cause ablation of outer layers of skin.
• Radio frequency has also been utilized as a means of transport of drug
through skin by virtue of its ability to create microchannels across
stratum corneum.
Examples:
• Sintov et al observed significant enhancement of two drugs namely
granisetron and diclofenac after pretreatment of rat skin with radio
frequency electrodes.
• RF-Microchannel technology which is developed by TransPharma of
Israel uses such a ‘cell ablation’ mechanism which is produced by
ViaDerm RF-Microchannel Device. This technology had been
successfully used to deliver diclofenac sodium, human growth hormone,
granisteron HCl, testosterone, insulin. ANUSHA NADIKATLA

35. JET PROPELLED PARTICULATE DELIVERY
This is another approach to enhance the permeability of drug through skin; this
technology uses high velocities to force particles across the stratum
corneum.The transdermal jetinjectors push drug molecules into the skin by
creation of a high-velocity jet (> 100 m/s) of compressed gas (usually helium)
that accelerates through the nozzle of the injector device, carrying with it drug
particles from the cartridge it disrupts on its passage into the nozzle.
Examples:
• Insulin has been one of the first molecules to appear in the clinical literature
relating to the use of jet injectors.
• Jet injectors continue to find application in the delivery of DNA or protein
vaccines, lidocaine and midazolam through the skin. Results of the clinical
testing of jet DNA vaccination show that DNA vaccines could induce both
antibody and cell mediated immune responses in humans
• Gas based injectors is being developed by Bioject (Biojector 2000) and
Powder ject (powder based injection).
• Needle-less jet injectors combine the advantages of transdermal and
parenteral drug delivery methods. ANUSHA NADIKATLA

36. SUPER SATURATION
• Thermodynamic activity of drug can be increased by employing
supersaturated systems. In this method,
• when saturated formulation is used, the thermodynamic activity of the
drug in the vehicle is increased above unity, thus enhancing the
permeability of topically applied formulations. Skin permeation was
directly related
• to the degree of saturation and was independent of the absolute
concentration of the drug.
Examples:
• Supersaturation was used to enhance the permeation of a lipophilic
model compound (a lavendustin derivative, LAP) through excised pig
skin in vitro Formulations at two degrees of saturation led, in general,
to a concomitant increase in drug delivery.
• Kondo et al also utilized supersaturation technology to enhance the
transdermal delivery of nifedipine in rats. ANUSHA NADIKATLA

37. PHOTOMECHANICAL WAVES
In photomechanical waves, the pressure pulses produced by ablation of a
material target (polystyrene) by Q-switched or mode-locked lasers are
utilized to enhance the skin permeability. The mechanism of
enhancement of photochemical wave is not very clear but on microscopic
investigation it was found to act by producing changes in the lacunar
system which results in the formation of transient channels through the
stratum corneum.
Examples: This enhancement technique has produced 80% reduction in blood
glucose in diabetic rats when insulin was delivered through the rat skin using
photochemical wave.
• Terakawa et al, evaluated the tissue alterations potential of photomechanical
waves used for gene delivery on the basis of immunohistochemistry and
electron microscopy they observed no noticeable tissue alteration under the
optimum laser irradiation conditions used for therapeutic gene delivery to a
skin graft, demonstrating low invasiveness of our photomechanical waves
based gene transfection. ANUSHA NADIKATLA

38. Basic design of photomechanical wave delivery devices
A drug reservoir backed with a
laser target material (eg black
polystyrene) is placed on the skin.
A laser is fired over the application
site which hits the target material
resulting in the formation of
photomechanical waves which are
hypothesized to increase the
permeability of the stratum
corneum allowing the facilitated
passage of drug molecules from
the reservoir into the skin.
ANUSHA NADIKATLA

39. CHEMICAL ENHANCERS
• Chemicals or combination of chemicals that can act as permeation
enhancers are also known as sorption promoters or accelerants.
• These agents partition into, and interact with, the stratum corneum
constituents to induce a temporary, reversible increase in the skin
permeability.
• Different classes of penetration enhancers, including surfactant, fatty
acids, terpenes, and solvents have already been investigated. However
only a small number of chemical enhancers have been shown to
induce significant enhancement of drug transport and also many of
them are found to have skin irritation ability.
• Some of the more desirable properties for penetration enhancers are;
they should be nontoxic, non-irritating and nonallergenic, should work
unidirectionally, compatible with both excipients and drugs, should
have no pharmacological activity, and lastly cosmetically acceptable.
ANUSHA NADIKATLA

40. The selection of a permeation enhancer should be based on:
• Its efficacy in enhancing skin permeation.
• Its dermal toxicity.
• Its physicochemical and biologic compatibility with the system’s other
components.
MECHANISM
ANUSHA NADIKATLA

41. CHEMICAL PENETRATION ENHANCERS WITH THEIR
MECHANISMS OF ACTION ANUSHA NADIKATLA

42. ANUSHA NADIKATLA

43. ANUSHA NADIKATLA

44. COMBINATORIAL ENHANCEMENT TECHNIQUES FOR
TRANSDERMAL DELIVERY
• Application of a single enhancer may not yield the desire flux to achieve the
therapeutically effective plasma concentration of the active substance;
intervention may be required to use combination of penetration enhancement
strategies to achieve the target flux such as iontophoresis and chemical
enhancers.
• It is reported that iontophoresis of 5-fluorouracil can be combined with
electroporation and laser treatment. Up to five fold increases in flux of
leutenising hormone releasing hormone was reported using skin
electroporation followed by iontophoresis.
• It is possible to achieve synergistic enhancement of large peptides like
insulin by combination of terpenes (chemical enhancers) with iontophoresis.
Chemical enhancers like Benzalkoniumchloride exerted a synergistic effect
on the iontophoretic delivery of anionic enoxacin which is an
azafluoroquinolone antibacterial agent used in the treatment of urinary
tractinfections and gonorrhea.
• Additive effect of ultrasound and iontophoresis was also reported with 56-
fold enhancement observed for transdermal transport of heparin.
Electroporation with chemical enhancement methods has been found most
effective for microparticles and for large macroparticles such as, heparin,
oligonucleotides, DNA, vaccines and insulin. ANUSHA NADIKATLA

45. DESIGN OF TRANSDERMAL PATCHES
Transdermal patch is a dosage form which is topically administered in
the form of patches that delivers drug for systemic effect at
predetermined and controlled rate.
Basic components
• Polymer matrix / drug reservoir
• Drug
• Permeation enhancers
• Pressure sensitive adhesive
• Backing laminates
• Release liner
• Other excipients like plasticizers and solvents ANUSHA NADIKATLA

46. DESIGN FEATURES OF TRANSDERMAL DRUG DELIVERY
SYSTEMS
TDDSs are designed to support the passage of drug substances from the
surface of the skin through its various layers and into the systemic
circulation. Transdermal drug delivery systems may be constructed of a
number of layers, including:
An occlusive backing membrane to protect the system from
environmental entry and from loss of drug from the system or moisture
from the skin;
The drug at the skin-site;
A release liner, which is removed before application and enables drug
release;
An adhesive layer to maintain contact with the skin after application.
ANUSHA NADIKATLA

47. ANUSHA NADIKATLA

48. POLYMERS
Polymers are the backbone of transdermal drug delivery system which control
the release of the drug from the device. Polymer matrix can be prepared by
dispersion of drug in liquid or solid state synthetic polymer base. polymers used
in transdermal drug delivery systems should be:
 Stable
 Compatible
 Nonreactive with drug and other components of the system.
 Should provide effective release of the drug throughout the device.
 They should be easily fabricated to desired product.
 Polymers and degradation products should be nontoxic ,non antigenic to
host.
Polymers used in transdermal drug delivery system can be classified as:
1) Natural polymers: Cellulose derivatives, shellac, waxes, gums, etc
2) Synthetic elastomers: Polybutadiene, silicon rubber, etc
3) Synthetic polymers: Polyvinylalcohol, polyvinylchloride, etc
ANUSHA NADIKATLA

49. ACTIVE INGREDIENT
The transdermal route is an extremely best route for the delivery of drugs
which undergo extensive first pass metabolism, drugs with narrow
therapeutic window or drugs with shorter half-life which causes non-
compliance due to frequent dosing. The best drug candidates for passive
adhesive transdermal patches must be:
• Non-ionic
• Daily dose (< 20 mg/day)
• Half-life (10 hours or less)
• Low molecular weight(less than 500 daltons)
• Skin permeability
• Adequate solubility in oil and water (log p-1to3)
• Low melting point(less than 200ᵒc)
• Toxicology profile (non-irritating and non-sensitizing to skin)
• Potent. ANUSHA NADIKATLA

50. PERMEATION ENHANCERS
• These are the chemical compounds that increase the permeability of stratum
corneum so as to attain higher therapeutic levels of drug candidate.
Penetration enhancers interact with structural components of stratum
corneum i.e., proteins or lipids. They alter the protein and lipid packaging of
stratum corneum, thus chemically modify the barrier functions leading to
increased permeability. They disrupt the highly ordered stratum corneum
lipids and interact with cellular proteins. They improve partitioning of drug
co-enhancer or co-solvent into the stratum corneum.
• The amount of drug transported through unit area of skin per unit time
(Flux, J) is the product of diffusion coefficient of drug in the skin (D), the
skin-vehicle partition coefficient (K) and the drug concentration in the
vehicle or delivery system (C), divided by the thickness of skin (h).
Flux (J) = (DKC)/h
• In principle enhancers act by increasing drug partitioning (DK) in the
stratum corneum by acting as solvents to dissolve the skin lipids or to
denature skin proteins and increasing the drug solubility (C) in the
transdermal formulation / patch. ANUSHA NADIKATLA

51. PRESSURE SENSITIVE ADHESIVE
• It is a material that helps in maintaining an intimate contact between
transdermal system and the skin surface.
• It should adhere with not more than applied fingure pressure,
permanently tatchy, exert a strong holding force.
• Additionally it should be removable from the smooth surface without
leaving a residue.
• The selection of adhesive depends on patch design and drug
formulation.
• Ideally pressure sensitive adhesive should be biocompatible and
should not alter drug release.
ANUSHA NADIKATLA

52. BACKING LAMINATE
• The most comfortable backing laminate will be the one that exhibits
lowest modules or high flexibility, good oxygen transmission and a
high moisture vapour transmission rate.
• While designing a backing layer the consideration of chemical
resistance of the material is very important.
• Examples of some backing materials are vinyl, polyethylene and
Polyester films aluminised plastic -laminate,polyvinylalcohol.
ANUSHA NADIKATLA

53. RELEASE LINER
• During storage the patch is covered by a protective liner that is
removed and discharged immediately before the application of patch
to skin.
• As the liner is in intimate contact with the delivery system, it should
comply with specific requirements regarding chemical inertness and
permeation of the drug.
• Typically release liner is composed of a base layer which may be non-
occlusive or occlusive.
• Occlusive : poly ethylene
• Non-occlusive: paper fabric
OTHER EXCIPIENTS
• Various solvents such as chloroform, ethanol, and acetone are used to
prepare drug reservoir. Plasticizers such as poly ethylene glycol,
propylene glycol are added to provide plasticity to transdermal patch
ANUSHA NADIKATLA

54. 1. Foil covertrip 2. Drug matrix 3. Release liner 4. Foil baseplate 5.
Microporous tape 6. Absorbent Pad 7. Occlusive overlay
ANUSHA NADIKATLA

55. PREPARATION OF DIFFERENT TYPES OF TRANSDERMAL
PATCHES
Membrane permeation controlled
systems
Adhesive dispersion type systems
Matrix diffusion controlled systems
Micro reservoir type dissolution
controlled systems
ANUSHA NADIKATLA

56. ANUSHA NADIKATLA

57. MEMBRANE PERMEATION CONTROLLED SYSTEMS
• Membrane-controlled transdermal systems are designed to contain a
drug reservoir, or pouch, usually in liquid or gel form, a rate-
controlling membrane, and backing, adhesive, and protecting layers.
• In this type of system, drug reservoir is totally encapsulated in a
shallow compartment and a rate controlling polymeric membrane with
a defined drug permeablity property.
• Membrane-controlled systems have the advantage over monolithic
systems in that as long as the drug solution in the reservoir remains
saturated, the release rate of drug through the controlling membrane
remains constant.
• The intrinsic rate of drug release from this type of Drug Delivery
System is defined by equation:
ANUSHA NADIKATLA

58. ANUSHA NADIKATLA

59. ADHESIVE DISPERSION TYPE SYSTEMS
• The drug and other selected excipients, are directly incorporated into
the organic solvent based pressure sensitive adhesive solution, mixed,
cast as a thin film and dried to evaporate the solvents, leaving a dried
adhesive matrix film containing the drug and excipients.
• This drug in adhesive matrix is sandwiched between release liner and
backing layer.
• The intrinsic rate of drug release from this type of Drug Delivery
System is defined by equation:
ANUSHA NADIKATLA

60. ANUSHA NADIKATLA

61. MATRIX DIFFUSION CONTROLLED SYSTEMS
• Drug reservoir is prepared by dissolving the drug and polymer in a
common solvent.The insoluble drug should be homogenously
dispersed in hydrophilic or lipophilic polymer.
• Required quantity of plasticizer and permeation enhancer is then
added and mixed properly.
• The medicated polymer is molded into rings with defined surface area
and thickness over mercury followed by solvent evaporation.
• The film formed is then separated & mounted onto an occlusive base
plate in a compartment fabricated from a drug impermeable backing.
• Adhesive polymer is then spread along the circumference of the film.
• The intrinsic rate of drug release from this type of Drug Delivery
System is defined by equation:
ANUSHA NADIKATLA

62. ANUSHA NADIKATLA

63. MICRO RESERVOIR TYPE DISSOLUTION CONTROLLED
SYSTEMS
The drug reservoir is made of a homogenous dispersion of drug particles
suspended in an unleachable viscous liquid medium to form a paste like
suspension or gel or a clear solution of drug in a releasable solvent such
as ethanol.The drug reservoir formed is sandwiched between a rate
controlling membrane and backing laminate.
ANUSHA NADIKATLA

64. • The drug reservoir is formed by suspending the drug in water miscible
drug solubiliser
• Ex:poly ethylene glycol
• The drug suspension is homogenously dispersed in lipophilic polymer
forming thousands of unleachable microscopic drug reservoir. The
dispersion is quickly stabilised by immediately cross linking the
polymer chains in-situ which produces a medicated polymer disc of a
specific area and fixed thickness.
• The intrinsic rate of drug release from this type of Drug Delivery
System is defined by equation:
ANUSHA NADIKATLA

65. ANUSHA NADIKATLA

66. EVALUATION OF TRANSDERMAL THERAPEUTIC SYSTEMS
 Physicochemical evaluation
 In-vitro evaluation
 In vivo evaluation
PHYSICOCHEMICAL EVALUATION
• Thickness
• Uniformity of Weight
• Drug Content Determination
• Content Uniformity
• Moisture Content and Moisture Uptake
• Flatness
• Folding Endurance
• Tensile Strength
• Microscopic Studies
• Adhesive Studies
ANUSHA NADIKATLA

67. IN-VITRO DRUG RELEASE STUDIES:
Drug release mechanisms and kinetics are two characteristics of the
dosage forms. Following are various methods available for
determination of drug release rate of transdermal drug delivery systems :
» Paddle over disc
» The cylinder modified USP basket
» The reciprocating disc
» Diffusion cells
IN VIVO STUDIES:
In vivo evaluation studies are the true depiction of the drug performance.
The variables which cannot be taken into account during in vitro studies
can be fully explored during in vivo studies. The in vivo evaluation of
TDDS can be carried out by using animal models and human volunteers.
Skin irritation studies and stability studies are performed.
ANUSHA NADIKATLA

68. GENERAL CLINICAL CONSIDERATIONS IN THE USE OF TDDS
1. Percutaneous absorption may vary with the site of application.
2. TDDSs should be applied to clean, dry skin that is relatively free of
hair and not oily, irritated, inflamed, broken, or callused.
3. Use of skin lotion should be avoided at the application site, because
lotions affect skin hydration and can alter the partition coefficient
between the drug and the skin.
4. TDDSs should not be physically altered by cutting, since this destroys
the integrity of the system.
5. TDDS should be removed from its protective package, with care not to
tear or cut into the unit. ANUSHA NADIKATLA

69. 6. TDDS should be placed at a site that will not subject it to being rubbed
off by clothing or movement.
7. A TDDS should be worn for the full period stated in the product’s
instructions. Following that period, it should be removed and replaced
with a fresh system as directed.
8. The patient or caregiver should be instructed to cleanse the hands
thoroughly before and after applying a TDDS.
9. If the patient exhibits sensitivity or intolerance to a TDDS or if undue
skin irritation results, the patient should seek reevaluation.
10. Upon removal, a used TDDS should be folded in half with the
adhesive layer together so that it cannot be reused.
ANUSHA NADIKATLA

70. APPLICATIONS OF TRANSDERMAL THERAPEUTIC
SYSTEMS
• NSAIDS formulated as TDDS, can overcome gastric lesions
associated with oral dose.
• Drugs used for long term dosing in chronic diseases e.g:captopril,
verampril, terbutaline sulphate which have short biological half-life
and affected by first pass metabolism can be formulated as TDDS.
• Nimesulide in sodium alginate transdermal gel can provide better
analgesic and anti-inflammatory activity and avoid adverse effects
associated with long term treatment with high oral dose.
• Nitroglycerin patches are sometimes prescribed for treatment of
angina pectoris.
• Rivastigmine an alzheimers medication was formulated into patch
form under the brand name-EXELON.
ANUSHA NADIKATLA

71. ANUSHA NADIKATLA

72. ANUSHA NADIKATLA

73. FUTURE PROSPECTS
Improved delivery has been shown for drugs of differing lipophilicity
and molecular weight including proteins, peptides, and oligonucletides
using electrical methods (iontophoresis, electroporation), mechanical
(abrasion, ablation, perforation), and other energy-related techniques
such as ultrasound and needless injection. However, for these novel
delivery methods to succeed and compete with those already on the
market, the prime issues that require consideration include device design
and safety, efficacy, ease of handling, and cost-effectiveness. With
advancements in research, patients may shortly have small pocketsize
sonicators used to ‘inject’ drugs whenever required. In addition, these
devices could be attached with sensors that can scrutinize drug
concentrations in the systemic circulation to formulate a self-controlled
drug delivery method. Drug release systems aided by ultrasound may be
able to provide slow release of vaccines such as that for tetanus, or for an
AIDS vaccine. In near future, it would be fascinating to amalgamate
microneedles approach with a microchip to control the release of the
drug through the needles. ANUSHA NADIKATLA

74. CONCLUSION
Traditional transdermal patches have been available for more
than 25 years, and they have a proven history of success. Some
promising technologies like iontophoresis, electroporation, microneedles,
ultrasound, photomechanical waves etc. are now available, which can be
employed for improved and efficient transdermal delivery of even
challenging drugs like proteins, peptides and macromolecules.
Combining some of the above technologies (e.g. electroporation with
iontophoresis or ultrasound, or chemical enhancers) can significantly
increase transdermal permeation of the active substance, though the
practicality of the combination methods remains to be seen on pilot scale.
Possible commercialization of these methods may envisage to more
effective and consumer friendly transdermal drug delivery systems.
ANUSHA NADIKATLA

75. REFERENCES
[1] Y. W. Chien. Transdermal drug delivery and delivery systems, in: Y.W. Chien (Ed),
Novel Drug Delivery Systems, 2nd ed., Chapter 7, Marcel Dekker, New York, 1992, 301-
380.
[2] M. R. Prausnitz, S. Mitragotri, R. Langer. Current status and future potential of
transdermal drug delivery. Nat. Rev. Drug Discov., 2004, 3: 115-124.
[3] M. Aqil, Y. Sultana, A. Ali. Transdermal delivery of β-blockers. Expert opinion., 2006,
3: 405-418.
[4] B. J. Thomas, B. C. Finnin. The transdermal revolution. Drug Disc. Today, 2004, 9:
697-703.
[5] B. C. Finnin, T. M. Morgan. Transdermal penetration enhancers: applications,
limitations, and potential. J. Pharm. Sci., 1999, 88: 955-958.
[6] R. H. Guy. Current status and future prospects of transdermal drug delivery. Pharm.
Res., 1996, 13:1765-1769.
[7] B. W. Barry. Novel mechanisms and devices to enable successful transdermal drug
delivery. Eur. J. Pharm. Sci., 2001, 14: 101-114.
[8] T. I. Degim. New tools and approaches for predicting skin permeability. Drug Disc.
Today, 2006, 11: 517-523.
[9] M. Aqil, A. Ahad, Y. Sultana, et al. Status of terpenes as skin penetration enhancers.
Drug Disc. Today, 2007, 12:1061-1067.
[10] R. H. Bogner, M. F. Wilkos. Transdermal drug delivery part 2: upcoming
developments. U.S. Pharmacist., 2005, 28:8-10. ANUSHA NADIKATLA

76. ANUSHA NADIKATLA