TRANSDERMAL DRUG DELIVERY SYSTEM

WWEELLCCOOMMEE
1
T.B.EKNATH BABU (T.B.E.K.B)
STUDENT AT ARULMIGU KALASALINGAM COLLEGE OF
PHARMACY..

 IInnttrroodduuccttiioonn
 Transdermal drug delivery is hardly an old technology, since 1800’s and
the technology is no longer just adhesive patches. Due to recent advances
in technology and the ability to apply the drug to the site of action without
rupturing the skin membrane, transdermal route is becoming a widely
accepted route of drug administration.
 Over the last two decades more than 35 Transdermal patch products have
been approved in US.
 Definition: Transdermal drug delivery system can deliver the drugs
through the skin portal to systemic circulation at a predetermined rate and
maintain clinically the effective concentrations over a prolonged period of
time.
T.B.EKNATH 2 BABU (T.B.E.K.B)

Potential advantages of TDDS
 Avoids chemically hostile GI environment (drug degradation in acidic
and basic environments is prevented).
 No GI distress and the factors like Gastric emptying, intestinal motility,
transit time, donot effect this route as in oral route.
 Avoidance of significant presystemic metabolism (degradation in GIT
or by the liver) and therefore need lower doses.
 Allows effective use of drugs with short biological half-life.
 Allow administration of drugs with narrow therapeutic window
because drug levels are maintained within the therapeutic window for
prolonged periods of time.
 Reduced inter and intra patient variability.

 Enhance therapeutic efficacy, reduced fluctuations (rapid blood level
spikes-low and high) due to optimization of blood concentration – time
profile.
 Reduction of dosing frequency and enhancement of patient compliance.
 Provides controlled plasma levels of very potent drugs.
 Can provide adequate absorption of certain drugs.
 Avoids the risk and inconveniences of parenteral therapy (Painless method
of drug administration).
 Drug input can be promptly interrupted simply by removal of the patch
when toxicity occurs.
 Provides suitability of self medication.

Disadvantages of TDDS
 Drugs that require high blood levels cannot be administered – limited
only to potent molecules, those requiring a daily dose of 10mg or less.
 Transdermal administration is not a means to achieve rapid bolus type drug
input, rather it is usually designed to offer slow, sustained drug delivery.
 Adequate solubility of the drug in both lipophilic and aqueous
environments, to reach dermal microcirculation and gain access to the
systemic circulation.
 The molecular size of the drug should be reasonable that it should be
absorbed percutaneously.

 Tolerance inducing compounds are not an intelligent choice for this mode
of administration unless an appropriate wash out period is programmed in
between the dosing regimen.
 Difficulty of permeation of the drug through human skin –barrier function
of the skin.
 Skin irritation or dermatitis due to excipients and enhancers of drug
delivery system used for increasing percutaneous absorption is another
major limitation.
 Adhesive may not adhere well to all types of skin.
 Uncomfortable to wear.
 May not be economical.

Cross-section of human skin

Stratum Corneum (topmost 15 μm layer) is the main barrier

Pathways of drug penetration
1.Through stratum corneum 2.Transfollicular
3.9 T.B.EKNATH BABTU h(Tro.Bu.Eg.hK. Bsw) eat gland

Mechanisms of drug permeation
Hydrophilic drugs permeates by Intercellular pathway and Lipophilic
drugs permeates by Intracellular (Transcellular) mechanism.

Skin permeability kinetics
Fick’s First Law of Diffusion
 Percutaneous absorption of most drugs is a passive-diffusion process that
can be described by Fick’s first law of diffusion
dQ/dt = JT = PAΔC
 JT is the total flux transported through a unit area of skin per unit time in
steady state (μg/hr)
 A is area of the skin
 P is the effective permeability coefficient
 ΔC is the drug concentration gradient across the skin

Factors affecting percutaneous absorption
 Physicochemical factors
 Biological factors
 Formulation factors

Physicochemical factors of penetrant/drug
 Partition coefficient
 Solubility
 Ionization / pKa
 Molecular size and weight
 Stability or half-life

Biological factors
 PH of the environment
 Area of application
 Age, Sex, Race
 Condition of the skin
• Integrity and Thickness of stratum corneum
• Pathological conditions of skin
• Hydration
• Metabolism
• Temperature

Formulation factors
 Vehicle-solubility of the drug
• Lipophilicity of the solvent
• PH of the vehicle
 Composition of drug delivery system
• Surfactants

Drug properties
Dose deliverable : ≤ 10mg/day
Aqueous solubility : >1mg/ml
Lipophilicity : log P (1-3)
Molecular size : < 500 Daltons
Melting point : < 200°C
 Drug should not be an irritant to skin.
 The drug should not stimulate an immune reaction in the skin.
 Along with these properties the drug should be potent, having short half
life

Strategies for the enhancement of drug permeability

Drug vehicle interactions
1.Prodrugs
 The prodrug approach has been investigated to enhance
transdermal delivery of drugs with unfavourable partition
coefficients.
 The prodrug design strategy generally involves addition of a
pro-moiety to increase partition coefficient and solubility to
increase the transport of the drug in the stratum corneum.
 Upon reaching the viable epidermis, esterases release the
active drug by hydrolysis thereby optimizing concentration in
the epidermis.

2.Ion-pairs
 Charged drug molecules do not readily partition into or
permeate through human skin. Formation of lipophilic ionpairs
has been investigated to increase stratum corneum penetration
of charged species.
 This strategy involves adding an oppositely charged species to
the charged drug, forming an ion-pair in which the charges are
neutralized so that the complex can partition into and permeate
through the stratum corneum.
 The ion-pair then dissociates in the aqueous viable epidermis
releasing the parent charged drug that can diffuse within the
epidermal and dermal tissues.

Needle-free Jet
Injectors

Advantages
 Pain-free delivery — particles are too small to trigger pain
receptors on the skin.
 Improved efficacy and bioavailability.
 Targeting to a specific tissue, such as a vaccine delivered to
epidermal cells.
 Accurate dosing and Overcomes needle phobia.
 Safety — the device avoids skin damage or infection from
needles or splash back of body fluids.
 The PowderJect system fires solid particles (20–100μm)
through stratum corneum into lower skin layers, using a
supersonic shock wave of helium gas.
 Intraject is a development of the vaccine gun designed to
deliver liquids through skin without using needles.

2.Chemical permeation enhancers
 A substance that will increase the permeability of the
epithelial barrier by modifying its structure also termed as
accelerants or sorption promoters-can enhance drug flux.
Ideal Penetration Enhancer
Non-toxic, non-irritating, non-allergenic.
Immediate onset of increased permeability.
Immediate recovery of normal barrier properties upon removal
(reversible).
Physically and Chemically compatible with a wide range of drugs.

• Solvents - Ethanol, acetone, polyethylene glycol,
glycerol, propylene glycol, dimethyl
sulfoxide
• Surfactants - Brij30, brij72, Pluronic, Sodium lauryl
sulphate, Span 20, Tween 80.
• Azones - N- Acyl hexahydro-2-oxo-1H-azepines,
N-Alkylmorpholine-2,3-diones.
• Terpenes - Limonene, Carvone
• Fatty alcohols - Lauryl alcohol, linolenyl alcohol, oleic and
fatty acids acid and lauric acid.
• Miscellaneous - Lecithin, sodium deoxycholate, L-amino
acid, acid phosphatase,phospholipase &
calonase

Electrically Assisted methods
1.Ultrasound (Phonophoresis / Sonophoresis)
 Used originally in physiotherapy and sports medicine, applies
a preparation topically and massages the site with an
ultrasound source.
 The ultrasonic energy (at low frequency) disturbs the lipid
packing in stratum corneum by cavitation.
 Sonicators operating at frequencies in the range of 20kHz to
3MHz are available commercially and can be used for
Sonophoresis.
 Therapeutic ultrasound (1–3MHz) - for massage,
 Low-frequency ultrasound (23-40kHz) - in dentistry,
 High-frequency ultrasound (3–10 MHz) - diagnostic
purposes.

Enhanced Transdermal Permeation by Cavitation of
stratum corneum upon application of Ultrasound.

Ultrasound to Enhance Skin
Permeability

2.Iontophoresis
 The electrical driving of charged molecules into tissue, passes a small
direct current (approximately 0.5 mA/cm2) through a drug containing
electrode in contact with the skin. The most popular electrodes are
based on the silver/silver chloride redox couple.
Three main mechanisms enhance molecular transport:
 Charged species are driven primarily by electrical repulsion from the
driving electrode.
 Flow of electric current may increase the permeability of skin and
 Electroosmosis may affect uncharged molecules and large polar
peptides.
Limitations: Hair follicle damage is possible.

3.Electroporation
 Skin electroporation (electropermeabilization) creates transient
aqueous pores in the lipid by application of high voltage of
electrical pulses of approximately 100–1000 V/Cm for short
time(milliseconds). These pores provide pathways for drug
penetration that travel straight through the horny layer.
 This technology has been successfully used to enhance the
skin permeability of molecules with differing lipophilicity and
size including biopharmaceuticals with molecular weights
greater that 7kDA..

Basic components of TDDS
 Drug
 Polymer matrix
 Penetration enhancers
 Other Excipients
• Rate controlling membrane
• Adhesive
• Release liner
• Backing membrane

Types of Transdermal delivery devices

Transdermal matrix system
35
Rate controlling factors
Drug concentration in polymer matrix
Chemical nature of polymer matrix
Geometry of device
Polymers: PVC, PVP, Ethylene vinylacetate, microporous polypropylene.
Initially the drug is released rapidly, then rate declines as matrix is depleted.
Advantages: Sleeker and thinner, daily or multiple-day Applications.
Appropriate for drugs that penetrate readily and/or have low
dosage requirements.

Transdermal reservoir system
36
Rate controlling factors
Membrane thickness
Membrane permeability
Polymers: Cellulosic esters, polyamides or PVC.
Advantages: Used when matrix systems cannot penetrate
skin and drugs require significant penetration enhancement
and/or high dosage levels.

Release liners
 Protects the skin-contacting adhesive during storage.
 Substrate carries a very thin release coating.
 Provides low energy surface for ease of removal.
e.g.: polyester or polystyrene based films.
Backing material
 Contains formulation throughout shelf life and during wear period.
 They have laminate structure.
 They must be compatible with the formulation (nonadsorptive).
 They are occlusive and completely water impermeable in nature.
e.g.: Poly urethane films, Ethyl vinyl acetate, Poly olefins.
Adhesive layer
Acrylic copolymers, polyisobutylene and polysiloxane.

EEvvaalluuaattiioonn ooff TTDDDDSS
 Content, Content uniformity.
 In vitro release Vs Ex vivo permeation of active and
penetration enhancer – difussion cells.
 Residual solvent, residual monomer
 Release liner peel, adhesion.
 Mechanical properties
 Moisture absorption & Moisture loss
 Microbiology
 Pouch integrity
38 T.B.EKNATH BABU (T.B.E.K.B)

FFrraannzz DDiiffffuussiioonn CCeellll
39 T . B .E K SNkAiTnH: B RABaUt a(Tb.Bd.Eo.mK.Bin) al, Rabbit, Porcine, Human cadaver

Mechanical properties eevvaalluuaattiioonn bbyy uullttrraa tteesstteerr

Moisture aabbssoorrppttiioonn && MMooiissttuurree lloossss ssttuuddiieess
 Moisture absorption study: Saturated solution of Alcl3
(79.50% RH)/ 3 days.
• Moisture loss study: Patches were placed in a desiccator
containing Cacl2 at 40oC/24 hr.

Transdermal patches available in the
market

Marketed Products of Modified Transdermal Drug Delivery
Technologies

Conclusion
 Transdermal drug delivery technologies are becoming one of
the fastest growing sectors within the pharmaceutical industry.
 Advances in drug delivery systems have increasingly brought
about rate controlled delivery with fewer side effects as well
as increased efficacy and constant drug delivery.
 The market value for transdermal delivery was $12.7 billion in
2005, and is expected to increase to $21.5 billion in the year
2010 and $31.5 billion in the year 2015 – suggesting a
significant growth potential over the next 10 years.

References
 Controlled drug delivery –concepts and advances – by S.P.Vyas
R.K.Khar.
 Encyclopedia of pharmaceutical technology -third edition
edited by James Swarbrick volume-4 Microsphere Technology
and Applications by Diane J. Burgess and Anthony J. Hickey.
 Controlled and Novel drug delivery edited by N.K.Jain reprint
2007
 Encyclopedia of controlled drug delivery volume 2
encyclopedia of controlled drug delivery
 Asian Journal of Pharmaceutical and Clinical Research
transdermal drug delivery system: a review p. k.gaur,s. mishra,
s. purohit, k. dave..

 European Journal of Pharmaceutical Sciences Review -Novel
mechanisms and devices to enable successful transdermal drug
delivery by B.W. Barry.
 Transdermal drug delivery- penetration enhancement
techniques- Heather A.E. Benson.
 Microneedles : The option for painless delivery by Geeta M
Patel.

TRANSDERMAL DRUG DELIVERY SYSTEM

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TRANSDERMAL DRUG DELIVERY SYSTEM