transdermal drug delivery systems - a writeup

TRANSDERMAL DRUG

DELIVERY SYSTEMS 2014

A review write up covering major portion in TDDS includes, introduction,

factors, formulations & evaluation aspects..

AL AMEEN COLLEGE OF PHARMACY

Bangalore

TABLE OF CONTENTS

Contents

Introduction ______________________________________________________________________________________________ 1

Objective __________________________________________________________________________________________________ 1

Advantages _______________________________________________________________________________________________ 1

Disadvantages ____________________________________________________________________________________________ 2

Characteristics of Ideal TDDS ___________________________________________________________________________ 2

Examples of TDDS _______________________________________________________________________________________ 2

Skin (Function, Structure, Mechanism, Permeation – Mechanism, Overcome, Factors) ____________ 3

General Components of TDDS__________________________________________________________________________ 11

Formulation Approaches in TDDS _____________________________________________________________________ 15

Evaluation of TDDS _____________________________________________________________________________________ 20

Evaluation of Adhesive _________________________________________________________________________________ 22

Invitro Evaluation _______________________________________________________________________________________ 24

Invivo Evaluation _______________________________________________________________________________________ 28

Invitro-Invivo Correlation ______________________________________________________________________________ 28

References _______________________________________________________________________________________________ 28

AACP SURAJ C.

Page 1 2013-14 Advanced Drug Delivery System.

INTRODUCTION

Transdermal drug delivery systems utilize skin as a site for continuous drug administration into

the systemic circulation.

In simple words TDDS is defined as “a system, where the medicament leaves the

formulation and travels into the skin to provide its pharmacological action when applied

topically”.

Ex: patches, creams, gels, ointments.

The main aim is to achieve localized or systemic medication through topical application to intact

skin.

OBJECTIVES

1. CONTROLEED DRUG DELIVERY: Delivery of the drug at a controlled rate to the intact skin

for systemic absorption.

2. ALTERNATE ROUTE SPECIFICITY: System should possess proper physicochemical

characteristics to permit ready release of the drug and facilitate its partition from delivery

system in to stratum corneum.

3. STABILITY OF THE PATCH: The patch should adhere well to the skin and its physical size

and appearance and its placement on the body should not be deterrent to use.

4. NO ADVERSE EFFECTS: The system adhesive, vehicle and active agents should be non-

sensitizing and non-irritating to the skin.

5. SKIN STABILITY: System should not permit proliferation of the skin bacteria beneath

occlusion.

ADVANTAGES OF TDDS

i. Evades GI Conditions: Avoid GIT drug absorption difficulties caused by GIT pH, enzymatic

activity and drug interaction with food, drink or other orally administered drugs.

ii. Alternative to Oral Administration: Substitutes for oral administration of medication

when that route is unsuitable as in instance of vomiting or diarrhoea.

iii. No 1st Pass Metabolism: Avoids first pass metabolism of the drug i.e., the initial pass of a

drug substance through systemic and portal circulation following GI absorption.

iv. Convenience in administration: Avoid the risk and inconveniences of parenteral and oral

therapy and variable absorption metabolism associated with oral therapy.

v. Controllled release: Provides controlled plasma levels of very potent drugs.

vi. Good for Narrow therapeutic index drugs: Allows administration of drugs having narrow

therapeutic index.

AACP SURAJ C.


vii. Termination advantage: Provide capacity to terminate drug effects rapidly by removal of

drug application from surface of the skin.

viii. Emergency administration: Provide ease of administration of medication in emergencies

like unconscious, non-responsive, etc.

DISADVANTAGES OF TDDS

I. Irritating drugs: Unsuitable for drugs which are irritating or sensitizing to skin.

II. Adherence problem: Adhesive may not adhere well to all skin types.

III. Not for high blood levels: Drugs that require high blood levels cannot be administered.

IV. Inconvenience in wear: Uncomfortable to wear.

V. Economic value: May not be economical.

CHARACTERISTICS FOR IDEAL TDDS

a) Drug properties independent: the system should deliver the drug regardless to the size

and structure at the specified rate of delivery.

b) Selected delivery profile: delivery of the drug as per specified quantity – time profile.

c) Ease of Multiple drugs administration: ideal drug delivery system (IDDS) should be able

to deliver more than one therapeutic agent at a time.

d) Flexibility: the IDDS should have the capability for changing or adjusting the rate and

amount of delivery.

e) Target specific: this should focus towards drug transport to target site.

f) Ample Capacity: the system is capable of making repeated deliveries between replacements.

g) Conevenience: the TDDS raises or causes no new problems or concerns.

h) Reliability: the TDDS consists of few parts and has reliability in keeping with other delivery

systems.

i) Market place value: the TDDS offers high value by featuring maximum functionality at

minimum system complexity and cost.

EXAMPLES OF TDDS

TRANSDERM-NITRO: nitroglycerin once a day medication for angina – NOVARTIS.

TRANSDERM-SCOP: scopolamine for 72 hrs in the treatment of motion sickness –

NOVARTIS.

TRANS-VER-SAL: salicylic acid for topical keratolytic action – DOAK.

Several other for Antihypertensives, antiangina, antihistamine, anti-inflammatory, analgesic

and steroids.

AACP SURAJ C.


SKIN

SKIN FUNCTIONS:

1. Protective barrier for internal organs.

2. Ability to sense changes in temperature, pressure or pain.

3. Regulation of body temperature.

4. Excretion of fluids and electrolytes.

5. Stores fat.

6. Provides site for drug absorption.

STRUCTURE OF SKIN

The skin is a multilayered organ, complex in both structure and function.

THE LAYERS OF THE SKIN:

1) EPIDERMIS:

A. Composed of the stratum corneum and stratum germinatum.

B. The outermost stratum corneum layer (10-15µ) is quite dry and consists primarily of

blocks of cytoplasmic protein matrices (keratins) embedded in the extracellular lipid.

C. The keratins containing cells known as corneocytes, has an interlocking arrangement.

D. The stratum cells are continuously replenished by the slow upward migration of cells

produced by the basal cell layers of stratum germinativum.

2) DERMIS:

A. Composed of a network of collagen and elastin fibers embedded in a muco-

polysaccharide matrix, which contains blood vessels, lymphatic and nerve endings,

thereby providing physiological support the epidermis.

B. It is well supplied by blood to convey nutrients, remove waste products, regulate body

temperature and pressure.

3) HYPODERMIS:

A. Subcutaneous fat layer is a sheet of fat – containing areolar tissue, known as superficial

fascia, attaching the dermis to underlying structures.

AACP SURAJ C.


MECHANISM OF ABSORPTION:

Primary mechanism of absorption is passive diffusion.

There are two potential routes of drug absorption.

1. Hair follicular/sweat glands (transfollicular):

Water soluble substances are diffused through skin appendages faster than that of

other layers of the skin.

Sweat glands and hair follicles act as shunt i.e., easy pathway for diffusion through

the rate limiting stratum corneum.

2. Stratum corneum (transepidermal):

Within the stratum corneum molecule penetrate either transcellularly or

intercellularly.

Intercellular region are filled with lipid rich amorphous materials. Two possible

ways of diffusion are,

a. Transcellular – diffusion occur through the cells.

b. Intercellular – diffusion occur through the intercellular space

present between the cells.

AACP SURAJ C.


AACP SURAJ C.


FUNDAMENTALS OF SKIN PERMEATION:

Kinetics for successful development of TDDS involves following steps:

1. Sorption by stratum corneum.

2. Penetration of drug through viable epidermis.

3. Uptake of drug by capillary network in dermal papillary layer.

HOW TO OVERCOME BARRIER- TDDS?

Two important layers in skin: the dermis & the epidermis.

- To circumvent this, it is required to engineer the drugs to be both water-soluble &

lipid soluble (best mixture is about 50 % of the drug being each)

- Outermost layer- epidermis 100 to 150 micrometers thick, has no blood flow &

includes the stratum corneum.

- S corneum =most imp to transdermal delivery →composition allows to keep water

within the body & foreign substances out.

- Stratum corneum = thin, tough, relatively impermeable membrane →usually the rate

limiting step in TDDS.

- Dermis: (Beneath epidermis), dermis contains system of capillaries that transport

blood throughout the body. If the drug is able to penetrate the stratum corneum, it can

enter the blood stream. Passive diffusion =occurs too slowly for practical use.

- “Lipid-soluble substances” readily pass through →intercellular lipid bi-layers of cell

membranes.

- “Water-soluble drugs” →pass through skin because of hydrated intracellular

proteins”.

- Sweat ducts & hair follicles: Also paths of entry, but = considered rather

insignificant.

AACP SURAJ C.


Rate permeation across skin is given by:

dQ/ dt = Ps(Cd – Cr)

Where, dQ/dt – Rate of permeation.

Cd – Concentration of skin penetrants in donor compartment.

Cr – Concentration of skin penetrants in receptor compartment.

Ps – Permeability coefficient of skin tissue to penetrants.

Ps = Ks Dss / hs

Where, Ks – Partition coefficient for interfacial partitioning of the penetrant molecule from solution

medium.

Dss – Apparent diffusivity for steady state diffusion of penetrant molecule through a thickness of skin tissue.

hs – Total thickness of the skin tissues.

NOTE: If Ks/d, Dss & hs are constants then Ps is also constant.

Cd>> Cr ----- constant rate of drug permeation .

dQ/ dt = Ps Cd

To maintain the Cd at a constant value, the drug to be released at a rate (Rr) which is

always greater than the rate of skin uptake (Ra). i.e., Rr>>Ra.

The drug concentration on the skin surface (Cd) is maintained at a level greater than the

equilibrium solubility of the drug in the stratum corneum (Ces) i.e.,

Cd>>(Ces ) and the maximum rate of skin permeation is reached:

dQ/dt = Ps Ces

FACTORS AFFECTING SKIN PERMEATION:

The principle mechanism across mammalian skin is by passive diffusion through transdermal

route at steady state. The following factor effects the permeability.

1. Biological factor

a) Skin age

b) Skin condition

c) Regional site

d) Skin metabolism

e) Circulatory effect

AACP SURAJ C.


f) Species difference

2. Physiological and pathological condition of the skin like

a. Reservoir effect of horny layer

b. Lipid film

c. Skin hydration

d. Skin temperature

e. Effect of vehicles

3. Physico-chemical property of drug molecules.

a. solubility and Partition coefficient

b. pH condition

c. polarity

d. crystallinity and melting point

e. penetrant concentration

f. molecular weight

4. Physiochemical properties of drug delivery system.

a. Release characteristic

b. Composition of drug delivery system

c. Permeation enhancer

1. Biological Barrier

Skin age:

Skin of foetus, young ones and elders are permeable than adult tissue.

Children’s are more susceptible for skin toxic effect of drugs and other additives in system.

Skin condition:

Skin is tough barrier to penetration but only when it is intact.

Many agents can damage tissue thereby promotes permeation.

Defective st. corneum results in increase permeability

Rational skin site:

Diffusion is faster in scrotal, trunk, arm region when compare to palm or foot.

Skin metabolism:

Catabolic enzyme activity in viable epidermis is substantial.

Infect the viable epidermis is metabolically active than dermis.

If the topically applied drug is subjected to biotransformation during skin permeation and

systemic bioavailability can be affected markedly.

Circulatory effects:

AACP SURAJ C.


Changes in peripheral circulation of blood flow through dermis could affect percutaneous

absorption.

Thus an increased blood flow could reduce time for a penetrant remains in dermis and so

raise the concentration gradient across the skin.

Species difference:

Different species of mammalian skin display wide difference in anatomy between common

laboratory animals.

2. Physiological and pathological effect

Reservoir effect of horny layer:

It is a deeper layer sometimes it acts as depot.

And modify transdermal permeation characteristics of drugs.

Reservoir effect is due to irreversible binding of part of applied drug on skin.

This binding can be reduced by treatment of skin surface with anionic surfactants.

Lipid film:

Lipid film on skin surface act as protective layer to prevent removal of moisture from skin

and helps in maintaining barrier function of st.corneum.

Defatting of this film found to decrease transdermal absorption.

Skin hydration:

Enhances permeability.

Hydration can be achieved by covering or occluding skin with plastic sheeting, increases

hydration appear to open up dense, closely packed cells of skin and increases its porosity.

Skin temperature:

It is directly proportional to the temperature.

This is mainly due to – Thermal energy required for diffusivity.

- Solubility of drug in skin tissue.

- Increased vasodilatation of skin vessels.

- Occlusion of skin surface increases the temperature by 2-3 centigrade result in

increased molecular motion and skin permeation.

Effect of vehicle:

A vehicle can influence the percutaneous absorption by its potential effect on physical states

of skin.

Ex: Grease, paraffin bases are most occlusive while w/o bases are less. Humectants

in bases may dehydrate skin therefore decrease percutaneous absorption.

AACP SURAJ C.


3. Physico-chemical property of the drug molecules:

Solubility and partition coefficient:

Solubility of drug greatly influence on ability to penetrate in to skin.

Partition coefficient which is the index of relative solubilisation of drug in vehicle and

st.corneum has profound influence on transfer of drug from vehicle in to skin.

Drug solubility on the other hand determines concentration of drug present on absorption

site.

Thus can effect rate and extent of drug absorption.

The vehicle partition coefficient roughly proportional to relative solubility in st.corneum

and vehicle.

Skin permeation can be increase by increasing lipophilic character of drug, therefore drug

having both lipid and water solubility are well absorbed through skin.

pH condition:

Application of solution whose pH value are very high or very low can be destructive to skin

hence moderate pH favourable for drugs to penetrate through skin.

The flux of ionisable drugs can be affected by changes in pH that alters the ratio of charged

and uncharged species and their skin permeability.

Penetration concentration:

Generally higher the concentration of dissolved drug in vehicle faster the absorption.

At conc. higher than the solubility excess solid drug function as reservoir and helps to

maintain a constant drug for prolonged period of time.

Crystallinity and melting point:

The concentration of drug in any medium is related to heat of fusion and melting point.

According to theory, the solubility of the drug is related to two important thermodynamic

parameter, heat of fusion and melting point.

Hard crystalline material with enthalpies of fusion are less soluble than soft, low melting

compounds.

Hydrophobic molecules generally have low degree of crystallinity and owing to the very

small net negative free energy of hydrophobic molecules in water, therefore hydrophobic

drugs are low solubility in water.

Polarity:

The polarity of a drug molecule affect its skin permeability by imparting the partition co

efficient.

AACP SURAJ C.


4. Physico-chemical properties of drug delivery system:

Release characteristic:

Solubility of drug in the vehicle determines release rate.

The mechanism of drug release depends on,

-whether drug molecules are dissolve or suspended in delivery system.

- Interfacial partition coefficient of drug from delivery system to skin tissue.

- pH of the vehicle.

Composition of drug delivery system:

It not only affects the rate of drug release but also permeability of st,corneum by means of

hydration mixing with skin lipids or other sorption promoting effects.

Eg: Methyl salicylates is more lipophilic than its parent acid. When applied to skin from

fatty vehicle, the methyl salicylates yielded higher percutaneous absorption.

Enhancement of skin permeation:

Permeation of most of the drugs can be improved by addition of permeation enhancer in to

the delivery system.

Because majority of drugs will not penetrate through skin at rate sufficiently high for

therapeutic efficiency.

COMPONENTS OF TDDS

The components of TDDS are:

1. Polymeric membrane

2. Drug reservoir

3. Permeation enhancers

4. Other excipients- Adhesive and backing membrane.

POLYMERIC MEMBRANE:

• Polymer controls the release of the drug from the device.

DRUG RESERVOIR

ADHESIVE

LAYER

DRUG-IMPERMEABLE

METALLIC PLASTIC

LAMINATE

RATE CONTROLING

POLYMERIC MEMBRANE

AACP SURAJ C.


• Molecular weight, physical characteristics and chemical functionality of the polymer must allow

the diffusion of the drug substances at a desirable rate.

• Should be chemically non-reactive or it should be an inert drug carrier.

• The polymer must not decompose on storage or during is shelf life.

• Polymer and it’s decompose product should not be toxic.

• Easy to manufacture and fabricate into desired product.

• Mechanical properties of polymer should not deteriorate excessively.

• The cost of the polymer should not be excessively high or inexpensive.

Examples of polymers:

1. Natural Polymers:

E.g. cellulose derivatives, zein, gelatin, shellac, waxes, gums, natural rubber and

chitosan etc.

2. Synthetic Elastomers:

E.g.: polybutadiene, hydrin rubber, polyisobutylene, silicon rubber, nitrile, acrylonitrile,

neoprene, butylrubber etc.

3. Synthetic Polymers:

E.g. polyvinyl alcohol, polyvinyl- chloride, polyethylene, Polypropylene, polyacrylate,

polyamide, polyurea, polyvinylpyrrolidone, polymethyl-methacrylate

DRUG RESERVOIR:

Drug reservoir can be prepared by dispersion of drug in liquid or solid state synthetic polymer

base.

Drug reservoir may be in,

- Reservoir system

- Matrix system

- Microreservoir system

The important drug properties that affect its diffusion from devices as well as across the skin

include molecular weight, chemical functionality and physical properties.

1. PHYSICO-CHEMICAL PROPERTIES OF DRUG:

o Should have molecular weight less than 500 Daltons.

o Should have affinity for both lipophilic and hydrophilic phase.

o Should have low melting point.

2. BIOLOGICAL PROPERTIES OF DRUG:

o Should be potent with daily dose of few mg/day.

o Should have short half-life.

AACP SURAJ C.


o Drugs must not induce irritant or allergic response

o Drugs which degrade in the GIT or are in activated by hepatic first pass effect are

suitable candidates.

o Drugs which have to be administered for long period of time or which causes

adverse effects to non-target tissues can also be formulated.

PERMEATION ENHANCERS

The compounds which promotes skin permeability by altering the skin as a barrier of flux of a

desired penetrant.

The flux J of the drug across the skin can be written as:

J = D. dc/dx

Where,

D – Diffusion coefficient.

C – Concentration of diffusing molecule.

dx – Spatial co-ordinate.

The concentration gradient is thermodynamically in origin and diffusion co-efficient is related

to size and shape of permeant and energy required to make a hole for diffusion.

IDEAL PROPERTIES OF PENETRATION ENHANCERS:

Pharmacologically inert.

Nontoxic, non-allergic and non-irritating.

Immediate and predictable action.

Upon removal, skin should immediately and fully recover its normal barrier

properties.

Compatible with all drugs and excipients

Odourless, elastic, colourless and inexpensive.

MECHANISM – PERMEATION ENHANCERS:

They act by three mechanisms:

A. Reduces the resistance of stratum corneum by altering its physicochemical properties.

B. Alteration of hydration of stratum corneum.

C. Affecting the structure of lipids and protein in intercellular channel through solvent action

or denaturation and sometimes carrier mechanism is observed.

TYPES – PERMEATION ENHANCERS:

1. CHEMICAL PENETRATION ENHANCERS: The various types of chemical penetration

enhancers are-

AACP SURAJ C.


Enhancers include a wide range of chemical entities that increase skin permeability,

such as sulphoxides, alcohols, polyols, alkanes, fatty acids, esters, amines and amides,

terpenes, surfactants, cyclodextrin, water etc., some of them are:

a) Solvents or water: acts by hydrating the stratum corneum, chemically inactive and non-

damaging.

E.g. Urea, pyrrolidones.

b) Lipid modifiers: they interact with organised intercellular lipid of horny layer and increase

permeability of skin.

E.g. Ethanol.

c) Protein modifiers: surfactants interact with keratin to open dense keratin structure and make

it permeable.

E.g. Dimethyl sulfoxide.

d) Partitioning promoters: increase partitioning of the drug into horny layer.

E.g. Propylene glycol.

e) Ion pairs: lipophilic ion pair is made by adding suitable opposite charge to drug. This complex

readily penetrates skin.

E.g. Anionic and cationic surfactants.

f) Prodrug: some drugs do not pass horny layer easily due to physicochemical properties of drug

and skin, so prodrug with optimal partition coefficient has been employed.

Eg. Steroids and anti-inflammatory agents.

g) Liposome: colloidal drug particles are made with phospholipids and cholesterol to increase

permeability.

2. PHYSICAL PENETRATION ENHANCERS: * (given in detail about 3 types in end)

a) Electroporation: this includes short duration voltage to increase permeability, creating

hydrophilic pores in the skin and increase the penetration of the drug. The pulse of 100V is

applied per millisecond.

E.g., calcitonin

b) Sonophorosis: ultrasound pulses are passed through the probe into the skin fluidizing the lipid

bilayer by the formation of bubbles caused by cavitation. The force of cavitation causes the

formation of holes in the coenocytes, enlarging of intercellular spaces and perturbation of

stratum corneum lipids.

c) Laser ablation: utilizes high power pulses from a laser source and vaporizes the stratum

corneum, creating discrete permeable windows through which the drug molecules passes

easily.

AACP SURAJ C.


d) Needle array: Needles of approximately with or without center hollow channels are placed onto

the skin surface to penetrate the stratum corneum and epidermis without reaching the nerve

endings present in the upper dermis.

Eg: These needles are made up of silicon or hollow metals.

e) Ionotophoresis: the basic principle of iontophoresis is a small current is applied to the skin.

This provides the driving force to enable penetration of the charged molecule into the skin. A

drug reservoir is placed on the skin under the active electrode with same charge as the

penetrant.

f) Stratum corneum removal: This involves the removal of stratum corneum by adhesive tape to

increase the drug penetration.

g) High velocity particles: this includes powder jet system which fires solid particles through

horny layer to lower skin layer, using supersonic shockwaves of helium gas at high pressure. It

is pain free, target delivery, fast release and safe on skin.

OTHER EXCIPIENTS:

1. ADHESIVES

Should not irritate or sensitize skin or cause imbalance in normal skin flora during its contact

time with skin.

Should adhere to skin aggressively during dosing interval without its position being disturbed

by activities like bathing, exercise etc.

Should not leave an un-washable residue on skin.

Should have an excellent contact with skin at macroscopic and microscopic level.

Pressure sensitive adhesives are used.

Eg. Polyisobutylenes, acrylic acids and silicones.

2. BACKING MEMBRANE:

Are flexible and provide good bond to drug reservoir.

Prevent the drug leaving the dosage form from the top and accept printing.

Eg. Metallic plastic laminate, plastic backing with absorbent pad and occlusive are plate

(aluminium foil).

FORMULATION APPROACHES IN TDDS

1. Membrane Moderated TDDS

2. Adhesive Diffusion Controlled TDDS

3. Matrix Dispersion TDDS

4. Microreservoir Type TDDS

AACP SURAJ C.


MEMBRANE MODERATED TDDS:

The drug reservoir is totally encapsulated in a shallow compartment molded from a drug-

impermeable metallic plastic laminate and a rate controlling polymeric membrane.

The drug reservoir, the drug is either dispersed in a solid polymer matrix (e.g polyisobutylene)

or suspended in an unleachable, viscous liquid medium.

E.g., silicone fluid to form a paste like suspension or dissolved in a releaseable solvent

(eg. Alkylalcohol).

The rate limiting membrane can be either micro-porous or non-porous in nature (ethylene-

vinyl acetate).

On the external surface of the polymeric membrane, a thin layer of drug compatible,

hypoallergenic adhesive polymer like silicone or polyacrylate adhesive is applied.

The rate of drug release from this type of transdermal drug delivery system can be adjusted by

varying the polymer composition, permeability coefficient and thickness of the rate limiting

membrane and adhesive.

The intrinsic rate of drug release from this type of drug delivery system is defined by:

OR

dQ/dt = CR 1/Pm + 1/Pa where,

CR -the drug concentration in the reservoir compartment.

Pa and Pm -permeability co-efficients of the adhesive layer and rate-controlling

membrane.

Pm and Pa are defined as :

DRUG RESERVOIR

ADHESIVE

LAYER

DRUG-IMPERMEABLE

METALLIC PLASTIC

LAMINATE

RATE CONTROLING

POLYMERIC MEMBRANE

AACP SURAJ C.


Pm = Km/r .Dm/δm

Pa = Ka/m. Da /δa

Where,

Km/r and Ka/m – partition coefficients for the interfacial partitioning of the drug from

the reservoir to the membrane and from the membrane to the

adhesive.

Dm and Da – diffusion co-efficient in the rate controlling membrane and adhesive

layer.

δa and δm – are the thickness of the rate controlling membrane and adhesive layer.

Example of formulation: The membrane permeation-controlled transdermal drug delivery

has been applied to the development of transdermal system for controlled percutaneous

absorption of estradiol and prostaglandin derivative.

ADHESIVE DIFFUSION CONTROLLED TDDS:

Simpler version of membrane moderated drug delivery system.

The drug reservoir in a compartment is fabricated from a drug-impermeable metallic plastic

backing.

The drug reservoir is formulated by dispersing the drug in an adhesive polymer and then

spreading the medicated adhesive, by solvent casting, onto a flat sheet of drug impermeable

metallic plastic backing to form a thin drug reservoir layer.

Over the drug reservoir layer, layers of non-medicated, rate-controlling adhesive polymer of

constant thickness are applied to produce an adhesive diffusion-conrolled drug delivery

system.

The rate of drug release is defined by:

dQ/dt = Ka/r .Da.CR /δa

AACP SURAJ C.


Where,

Ka/r – partition coefficient for interfacial partitioning of drug from the reservoir to

adhesive layer.

Examples: This system is best illustrated by development of

nitroglycerin-releasing transdermal system (Deponit system/Pharma-Schwartz)

and

isosorbide dinitrate-releasing transdermal system (Frandol tape/ Toaeiyo) for once

a day medication of angina pectoris.

MATRIX DISPERSION – TYPE SYSTEMS

The drug reservoir is formed by homogeneously dispersing the drug solids in a hydrophilic

or lipohilic polymer matrix and the medicated polymer is molded into medicated disc with a

defined surface area and controlled thickness.

Drug-reservoir containing polymer disc is then glued onto an occlusive base plate in a

compartment fabricated from impermeable plastic backing.

The adhesive polymer is spread along the circumference to form a strip of adhesive rim

around the medicated disc.

The rate of drug release from the matrix dispersion type TDDS is defined as:

dQ/dt = (ACpDp/2t)1/2

Where,

A – initial drug loading dose dispersed in the polymer matrix.

Cp and Dp – are solubility and diffusivity of the drug in the polymer.

At steady state, a Q versus t drug release profile is obtained as defined:

Q/t = [(2A – Cp)CpDp]1/2

AACP SURAJ C.


Examples: This TDDS is exemplified by development of nitro-glycerin-releasing transdermal

system (Nitro-Dur system/Key), approved by FDA for once a day medication of angina

pectoris.

MICRO-RESERVOIR SYSTEMS:

It is a combination of the reservoir and matrix dispersion-type drug delivery systems.

The drug reservoir is formed by suspending the drug solids in an aqueous solution of water-

soluble polymer and dispersing the drug suspension in a lipophilic polymer by mechanical force

to form unleachable microscopic spheres of drug reservoirs.

This thermodynamically unstable suspension is stabilized by cross-linking the polymer chains

to produce a polymeric disc.

Example: Nitro glycerin – releasing transdermal system ( Nitrodisc system/ Searle) for once a

day treatment of angina pectoris.

The rate of drug release from the microreservoir drug delivery system is defined by:

Where,

Kl, Km and KP - are partition coefficients for the interfacial partitioning of drug in the

liquid compartment and the polymeric matrix.

Dl, DP and DS- drug diffusivities in the liquid compartment, polymer coating membrane

and elution solution.

Sl and SP – solubilities of the drug in the liquid compartment and polymer matrix.

δl, δP and δd – thicknesses of the liquid layer, polymer coating membrane and

hydrodynamic diffusion layer.

AACP SURAJ C.


β – is the ratio of the drug concentration at the inner edge of the interfacial barrier over

the drug solubility in the polymer layer.

EVALUATION OF TDDS

Transdermal drug delivery system requires systemic evaluation at various stages of its

development. These evaluation are described below:

Physico-chemical Evaluation

In vitro release study

In vivo Evaluation

Invitro-In vivo Correlation

PHYSICO-CHEMICAL EVALUATION

1. Thickness of the patch:

The thickness of the prepared patch is measured by using a digital micrometer at different point

of patch.

This determines the average thickness and standard deviation for the same to ensure the

thickness of the prepared patch

2. Weight uniformity :

The prepared patches are dried at 60°C for 4 h before testing.

A specified area of patch is to be cut in different parts of the patch and weighed in digital balance.

The average weight and standard deviation values are to be calculated from the individual

weights.

3. Folding endurance :

A specific area of strip is cut and repeatedly folded at the same place till it broke.

The number of times the film could be folded without breaking gave the value of folding

endurance.

4. Percentage moisture content :

The prepared patches are weighed individually and to be kept in a desiccator containing fused

calcium chloride at room temperature.

After 24 h, the films are to be reweighed and the percentage moisture content determined by

below formula………

Percentage moisture content (%) = [Initial weight – Final weight / Final weight] ×100

5. Percentage moisture uptake:

AACP SURAJ C.


The prepared patches are to be weighed individually and to be kept in a desiccator containing

saturated solution of potassium chloride in order to maintain 84% Rhesus factor (RH).

After 24 h, the films are to be reweighed and the percentage moisture uptake determined by the

formula

Percentage moisture content (%) = [Initial weight - Final weight / Final weight]×100

6. Water vapor permeability (WVP) evaluation:

Water vapor permeability can be determined by a natural air circulation oven.

The WVP can be determined by the following formula………….

WVP = W/A Where,

WVP = expressed in g/m2 per 24 h, W = the amount of vapor permeated through the patch expressed in g/24 h,

A = surface area of the exposure samples expressed in…….

m2.weight / initial wt × 100

7. Drug content:

A specified area of patch is to be dissolved in a suitable solvent in specific volume.

Then, the solution is to be filtered through a filter medium and the drug content analyzed with

the suitable method (UV or HPLC technique).

Then, the average of three different samples is taken.

8. Content uniformity test:

Ten (10) patches were selected and content determined for individual patches.

If 9 out of 10 patches have content between 85 to 115% of the specified value and one has

content not less than 75 to125% of the specified value, then transdermal patches pass the test

of content uniformity.

But if 3 patches have content in the range of 75 to 125%, then additional 20 patches are tested

for drug content. If these 20 patches have range from 85 to 115%, then the transdermal patches

pass the test.

9. Percentage elongation break test :

The percentage elongation break was determined by noting the length just before the break

point and determined from the formula………..

Elongation percentages = L1 - L2 × 100 L2

Where ,

L1 = final length of each strip;

L2 = initial length of each strip.

10. Flatness test:

AACP SURAJ C.


Three longitudinal strips were cut from each film at different portion like one from the center,

other one from the left side, and another one from the right side.

The length of each strip was measured, and the variation in length because of non-uniformity

in flatness was measured by determining percentage constriction, with 0% constriction

equivalent to 100% flatness.

Constriction (%) = I1- I2 × 100 I1 Where, I1 = initial length of each strip.

I2 = final length of each strip.

11. Polariscope examination:

This test is to be performed to examine the drug crystal from patch by polariscope.

A specific surface area of piece is to be kept on object slide and observe for drug crystal.

To distinguish whether the drug crystal are present in amorphous or crystalline form.

12. Stability studies:

Stability studies were conducted according to the International Conference on Harmonization

(ICH) guidelines by storing the TDDS samples at 40 ± 0.5°C and 75 ± 5% RH for 6 months.

The samples were withdrawn at 0, 30, 60, 90 and 180 days and analyzed suitably for the drug

content.

EVALUATION OF ADHESIVE Pressure sensitive adhesive are evaluated for the following properties:

1. Peel adhesion properties

2. Tack properties

o Thumb tack test

o Roll ball tack test

o Quick stick (peel-tack) test

o Probes tack test

3. Shear strength test

1. Peel adhesion properties

Peel adhesion is the force required to remove an adhesive coating from a test substrate.

It is important in transdermal devices because the adhesive should provide adequate contact of

device with the skin and should not damage the skin on removal.

Peel adhesion properties are affected by the molecular weight of the adhesive polymer, the type

and amount of additives and polymer composition.

AACP SURAJ C.


It is tested by measuring the force required to pull a single coated tape applied to a substrate at

an angle of 180°. No residue on the substrate indicates ‘adhesive failure’ which is desirable for

transdermal devices.

2. Tack properties

Tack is the ability of a polymer to adhere to a substrate with little contact pressure. It is

important in transdermal devices which are applied with finger pressure.

The tack tests include,……….

a. Thumb tack test:

This is a subjective test in which evaluation is done by pressing the thumb briefly

into the adhesive.

Experience is required for this test.

b. Roll ball tack test:

This test involves measurement of the distance that a stainless steel ball travels

along an upward-facing adhesive.

The less tacky the adhesive, the farther the ball will travel.

c. Quick stick (peel-tack) test:

The peel force required to break the bond between an adhesive and substrate is

measured by pulling the tape away from the substrate at 90° at a speed of 12

inch/min.

d. Probes tack test:

The force required to pull a probe away from an adhesive at a fixed rate is recorded

as tack(expressed in grams).

3. Shear strength test:

It is the measurement of the cohesive strength of an adhesive polymer.

Adequate cohesive strength of a device will mean that the device will not slip on application and

will leave no residue on removal.

It is affected by molecular weight as well as the type and amount of tackifier added.

Shear strength or creep resistance is determined by measuring the time it takes to pull an

adhesive coated tape off a stainless steel plate when a specified weight is hung from the from

the tape which pulls the tape in a direction parallel to the plate.

AACP SURAJ C.


IN VITRO EVALUATION OF TDDS

The paddle over disc method (USP apparatus V) can be employed for assessment of the release

of the drug from the prepared patches.

Dry films of known thickness were cut into definite shape, weighed, and fixed over a glass

plate(disc) with an adhesive.

The glass plate was then placed in a 500 ml of the dissolution medium or phosphate buffer (pH

7.4), and the apparatus was equilibrated to 32 ± 0.5°C.

The paddle was then set at a distance of 2.5 cm from the glass plate and operated at a speed of

50 rpm.

Samples (5 ml aliquots) can be withdrawn at appropriate time intervals up to 24 h and analyzed

by UV spectrophotometer or HPLC.

The experiment was performed in triplicate and the mean value calculated

IN VITRO SKIN PERMEATION STUDIES

An in vitro permeation study can be carried out by using diffusion cell on thick abdominal skin

of male Wurstar rats weighing 200 to 250 g.

Hair from the abdominal region is removed carefully by using an electric clipper.

The dermal side of the skin was thoroughly cleaned with distilled water to remove any adhering

tissues or blood vessels, equilibrated for an hour in dissolution medium or phosphate buffer pH

7.4 before starting the experiment.

It was placed on a magnetic stirrer with a small magnetic needle for uniform distribution of the

diffusant.

The temperature of the cell was maintained at 32 ± 0.5°C using a thermostatically controlled

heater.

The isolated rat skin piece was mounted between the compartments of the diffusion cell, with

the epidermis facing upward into the donor compartment.

Sample volume of definite volume was removed from the receptor compartment at regular

intervals, and an equal volume of fresh medium was replaced.

Samples were filtered through filtering medium and analyzed spectrophotometrically or using

HPLC.

Flux was determined directly as the slope of the curve between the steady-state values of the

amount of drug permeated (mg cm2) versus time in hours.

Permeability coefficients were deduced by dividing the flux by the initial drug load (mg cm2).

AACP SURAJ C.


KINETIC EVALUATION OF TRANSDERMAL THERAPEUTIC SYSTEMS

The release and skin permeation kinetics of drug from these technologically different

transdermal therapeutic systems can be evaluated, using a two-compartment diffusion cell

assembly, under identical conditions.

It is carried out by mounting, individually, the full-thickness abdominal skin, which has been

freshly excised from either human cadaver or hairless mouse, on an eight-cell Franz diffusion

assembly.

The drug delivery systems are then applied with their drug-releasing surface in intimate contact

with the stratum corneum surface of the skin.

The skin profile of the drug is followed by sampling the receptor solution at predetermined

intervals for a duration of up to 30h and assaying drug concentrations in the samples by a

sensitive analytical method, such as HPLC method.

In-vitro Drug Release Kinetics:

Using Franz diffusion cell assembly, the controlled release kinetics of drugs from these

technologically-different transdermal therapeutic system can be evaluated and compared.

E.g. :

The results indicated that nitroglycerin is released at a constant rate profile

Transderm-Nitro system (a membrane-moderated transdermal therapeutic system)

and Deponit system(an adhesive diffusion-controlled transdermal drug delivery

system).

The release rate of nitroglycerin from the Transderm-Nitro system is almost 3 times

greater than that from the Deponit system.

AACP SURAJ C.


This suggests that the rate controlling membrane of Deponit system plays a greater

rate-controlling role over the release of nitroglycerin than does the rate-controlling

membrane in the Transderm-Nitro system.

E.g. :

Similarly, the release rate of nitroglycerin from Nitro-Dur system(a matrix dispersion-

type transdermal therapeutic system) is about twice greater than that from Nitrodisc

system(a microreservior-type transdermal therapeutic system).

- Nitrodisc–2.443±0.136mg/cm2/day,

- Nitro-Dur–4.124±0.047mg/cm2/day,

- Transderm-Nitro–0.843±0.035mg/cm2/day,

- Deponit – 0.324±0.011mg/cm2/day.

In Vitro Skin Permeation Kinetics-Animal Model:

The skin permeation studies showed that all four transdermal therapeutic systems provide a

constant rate of skin permeation.

Ex:

A highest rate of skin permeation was observed with Nitrodisc system, which is no

different from the rate of skin permeation for pure Nitroglycerin.

For Nitro-Dur system the same rate of skin permeation was observed initially and

12hr later the rate slowed down.

On the other hand the rate of skin permeation of nitroglycerin delivered by

Transderm–Nitro was found to be to be 30% lower than the rate achieved by pure

nitroglycerin.

AACP SURAJ C.


The lowest rate of skin permeation was observed with Deponit system , which is only

37% of the skin permeation rate for pure nitroglycerin.

- Nitrodisc – 0.426 ± 0.024mg/cm2/day,

- Nitro-Dur – 0.408 ± 0.024mg/cm2/day,

- Tansderm-Nitro – 0.338 ± 0.17mg/cm2/day,

- Deponit – 0.175 ± 0.016mg/cm2/day.

In Vitro Skin Permeation Kinetics –Human Cadaver:

The permeation of nitroglycerin across the human cadaver skin was investigated for

Transderm-Nitro system and Nitro-Dur system.

The results indicated that the skin permeation of nitroglycerin through human cadaver

abdominal epidermis also follows the same kinetic profile as observed with hairless mouse

abdominal skin, suggesting that the hairless mouse skin could be an acceptable animal model

for human in the skin permeation kinetic studies of nitroglycerin.

AACP SURAJ C.


In Vivo Transdermal Bioavailability In Humans:

The transdermal bioavailability of nitroglycerin resulted from the 24-32hr topical

applications of various transdermal therapeutic system in human volunteers.

Results suggest that a prolonged, steady state plasma level of nitroglycerin is achieved within

1-2hr and maintained for a duration of at least 24hr as a result of continuous transdermal

infusion of drug at a controlled rate from the transdermal therapeutic system.

In-vitro – In-vivo Correlation:

To further examine the feasibility of using hairless mouse skin as animal model for studying

transdermal controlled permeation kinetics of drug across the human skin, the in vivo rate of

skin permeation should be determined for comparison.

It can be calculated from the steady state plasma level data using the following equation,

(Q /t)i.v = (CP)SS.Ke.Vd

Where,

Ke = first-order rate constant for elimination of drug and Vd is the apparent volume

of distribution of drug.

This in vivo - in vitro agreement provides additional evidence that hairless mouse skin could

be an acceptable animal model for studying skin permeation kinetics of systemically effective

drugs, like nitroglycerin, in humans.

AACP SURAJ C.


DELIVERY

SYSTEMS

HAIRLESS

MOUSE

HUMAN

CADEVER

IN VIVOd

Nitroglycerin alone 0.476a 0.312b -

Nitrodisc 0.426 - 0.473

Nitro-Dur 0.408 0.487c 0.412

Transderm-Nitro 0.338 0.461c 0.428

Deponit 0.175 - -

NOTE:

a determined from skin permeation studies of pure nitroglycerin across full-thickness hairless

mouse abdominal skin at 37°C.

b determined from an aqueous solution of nitroglycerin at 30°C.

C determined from skin permeation studies at 37°C using the epidermis isolated from human

cadaver abdominal skin.

REFERENCES

1. Y.W Chein, Novel Drug Delivery Systems, 2nd edition Marcel Dekker, New York .

2. Robinson, J.R., Lee V.H.L, Controlled Drug Delivery Systems, Marcel Dekker, New York.

p. 523 – 547.

3. Comprehensive Journal of Pharmaceutical Sciences Vol. 1(1), pp. 1 - 10, Feb. 2013

transdermal drug delivery systems - a writeup

Health & Medicine

advanced drug delivery

controleed drug delivery

drug effects

drug interaction

drug substance

drug transport

continuous drug administration

evaluation of tdds