transdermal drug delivery system

WELCOMEWELCOME

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

PHARMACY..

1

T.B.EKNATH BABU (T.B.E.K.B)2

IntroductionIntroduction

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.


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


1.Through stratum corneum 2.Transfollicular

3.Through sweat glandT.B.EKNATH BABU (T.B.E.K.B)9

Pathways of drug penetration

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 EnhancerNon-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

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Rate controlling factorsMembrane 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.

Evaluation of TDDSEvaluation of TDDS


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

Franz Diffusion CellFranz Diffusion Cell

T.B.EKNATH BABU (T.B.E.K.B)39 Skin: Rat abdominal, Rabbit, Porcine, Human cadaver

Mechanical properties evaluation by Mechanical properties evaluation by

ultra testerultra tester


Moisture absorption & Moisture loss Moisture absorption & Moisture loss

studiesstudies


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

Science

eknath babu t

drug lipophilicity

drug input

sustained drug delivery

drug concentration gradient

pathways of drug penetration1

skin integrity

skin membrane