Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM
Introduction:-
At present, the most common form of delivery of drugs is the oral route. While this has
the notable advantage of easy administration, it also has significant drawbacks -- namely
poor bioavailabiltity due to hepatic metabolism (first pass) and the tendency to produce
rapid blood level spikes (both high and low), leading to a need for high and/or frequent
dosing, which can be both cost prohibitive and inconvenient.
To overcome these difficulties there is a need for the development of new drug
delivery system; which will improve the therapeutic efficacy and safety of drugs
by more precise (iesitespecific) , spatial and temporal placement within
the body thereby reducing both the size and number of doses. New drug delivery
system are also essential for the delivery of novel , genetically engineered
pharmaceuticals (ie.peptides;proteins) to their site of action , without
incurring significant immunogenecity or biological inactivation. Apart from
these advantages the pharmaceutical companies recognize the possibility of repattening
successfull drugs by appling the concepts and techniques of controlled drug
delivery system coupled with the increased expense in bringing new drug moiety
to the market.One of the methods most often utilized has been transdermal
delivery - meaning transport of therapeutic substances through the skin for
systemic effect. Closely related is percutaneous delivery, which is transport
into target tissues, with an attempt to AVOID systemic effects.
There are two important layers in skin: the dermis and the epidermis.
The outermost layer, the epidermis, is approximately 100 to 150 micrometers
thick, has no blood flow and includes a layer within it known as the stratum
corneum. This is the layer most important to transdermal delivery as its
composition allows it to keep water within the body and foreign substances out.
Beneath the epidermis, the dermis contains the 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. A process known as passive diffusion,
which occurs too slowly for practical use, is the only means to transfer normal
RKDF COLLEGE OF PHARMACY Page 1

drugs across this layer. The method to circumvent this is to engineer

the drugs be both water-soluble and lipid soluble. The best mixture is
about fifty percent of the drug being each. This is because “Lipid-soluble
substances readily pass through the intercellular lipid bi-layers of the cell
membranes whereas water-soluble drugs are able to pass through the skin because of
hydrated intracellular proteins”. Using drugs engineered in this manner, much more
rapid and useful drug delivery is possible.( the stratum corneum develops a thin, tough,
relatively impermeable membrane which usually provides the rate limiting step in
transdermal drug delivery system. Sweat ducts and hair follicles are also paths of entry,
but they are considered rather insignificant.
Types of TDS
• Liquid Reservoir Patch
Drug in solution or suspension between the backing layer and a rate

controlling membrane
• Drug in Adhesive Patch
Drug dispersed in adhesive, in direct contact with skin
• Polymer Matrix Patch
Drug in solution or suspension dispersed within a polymer
• Multi-laminate Matrix Patch
Drug dispersed in adhesive in multi-layers separated by membranes.
TYPES OF TRANSDERMAL PATCHES
Four Major Transdermal Systems
1. Single-layer Drug-in-Adhesive

The Single-layer Drug-in-Adhesive system is characterized by the inclusion of

the drug directly within the skin-contacting adhesive. In this transdermal system
design, the adhesive not only serves to affix the system to the skin, but also
serves as the formulation foundation, containing the drug and all the excipients
under a single backing film. The rate of release of drug from this type of system
is dependent on the diffusion across the skin.
The intrinsic rate of drug release from this type of drug delivery system
is defined by
Cr
dQ/dT = ---------------------------
1/Pm + 1/Pa
Where, Cr is the drug concentration in the reservoir compartment and Pa and P m are the
permeability coefficients of the adhesive layer and the rate controlling membrane , Pm is
the sum of permeability coefficients simultaneous penetrations across the pores and the
polymeric material. Pm and Pa , respectively, are defined as follows.

Km/r . Dm
Pm = _____________
hm
Ka/m . Da
Pa = _____________
ha
where Km/r and Ka/m are the partition coefficients for the interfacial partitioning of drug
from the reservoir to the membrane and from the membrane to adhesive respectively; Dm
and Da are the diffusion coefficients in the rate controlling membrane and adhesive layer,
respectively; and hm and ha are the thicknesses of the rate controlling membrane and
adhesive layer, respectively.
2. Multi-layer Drug-in-Adhesive

The Multi-layer Drug-in-Adhesive is similar to the Single-layer Drug-in-Adhesive

in that the drug is incorporated directly into the adhesive. However, the multi-layer
encompasses either the addition of a membrane between two distinct drug-in-adhesive
layers or the addition of multiple drug-in-adhesive layers under a single backing
film.
The rate of drug release in this system is defined by:
Ka/r . Da
dQ/dt = ------------------------ Cr
ha
where Ka/r is the partition coefficient for the interfacial partitioning

of the drug from the reservoir layer to adhesive layer.(1,9)

3. Drug Reservoir-in-Adhesive
The Reservoir transdermal system design is characterized by the inclusion

of a liquid compartment containing a drug solution or suspension separated from
the release liner by a semi-permeable membrane and adhesive. The adhesive component
of the product responsible for skin adhesion can either be incorporated as a
continuous layer between the membrane and the release liner or in a concentric
configuration around the membrane.
The rate of drug release from this drug reservoir gradient controlled system
is given by:
Ka/r . Da
dQ/dt = --------------------- A ( ha )

ha ( t )
In the above equation, the thickness of the adhesive layer for drug molecules
to diffuse through increases with time ha (t). To compensate for this time dependent
increase in the diffusional path due to the depletion of drug dose by release,
the drug loading level is also increased with the thickness of diffusional
path A
4. Drug Matrix-in-Adhesive
The Matrix system design is characterized by the inclusion of a semisolid

matrix containing a drug solution or suspension which is in direct contact with
the release liner. The component responsible for skin adhesion is incorporated
in an overlay and forms a concentric configuration around the semisolid matrix.

The rate of drug release from this type of system is defined as :
½
dQ ACp Dp
------ = ----------------
dt 2t
where A is the initial drug loading dose dispersed in the polymer matrix and
Cp and Dp are the solubility and diffusivity of the drug
in the polymer respectively. Since, only the drug species dissolved in the polymer
can release, Cp is essentially equal to CR , where CR
is the drug concentration in the reservoir compartment.
The components of transdermal devices
1. Polymer matrix or matrices.

2. The drug
3. Permeation enhancers
4. Other excipients
1.Polymer Matrix
The Polymer controls the release of the drug from the device. Possible useful polymers
for transdermal devices are:
a) Natural Polymers:
e.g. Cellulose derivatives, Zein, Gelatin, Shellac, Waxes, Proteins, Gums and their
derivatives, Natural rubber, Starch etc.
b) Synthetic Elastomers:
e.g. Polybutadieine, Hydrin rubber, Polysiloxane, Silicone rubber, Nitrile, Acrylonitrile,

Butyl rubber, Styrenebutadieine rubber, Neoprene etc.
c) Synthetic Polymers:
e.g. Polyvinyl alcohol, Polyvinyl chloride, Polyethylene, Polypropylene, Polyacrylate,

Polyamide, Polyurea, Polyvinylpyrrolidone, Polymethylmethacrylate, Epoxy etc.
2.Drug

For successfully developing a transdermal drug delivery system,

the drug should be chosen with great care. The following are some of the desirable
properties of a drug for transdermal delivery.
Physicochemical properties
1. The drug should have a molecular weight less than approximately 1000 daltons.
2. The drug should have affinity for both – lipophilic and hydrophilic phases. Extreme
partitioning characteristics are not conducive to successful drug delivery via the skin.
3. The drug should have low melting point
Along with these propertiesthe drug should be potent, having short half life and be non
irritating.
3.Permeation Enhancers
These are compounds which promote skin permeability by altering

the skin as a barrier to the flux of a desired penetrant.These may conveniently be
classified under the following main headings:
a.Solvents
These compounds increase penetration possibly by swallowing the polar pathway and/or
by fluidizing lipids. Examples include water alcohols – methanol and ethanol; alkyl
methyl sulfoxides – dimethyl sulfoxide, alkyl homologs of methyl sulfoxide dimethyl
acetamide and dimethyl formamide ; pyrrolidones – 2 pyrrolidone, N-methyl, 2-
purrolidone; laurocapram (Azone), miscellaneous solvents – propylene glycol, glycerol,
silicone fluids, isopropyl palmitate.
b) Surfactants

These compounds are proposed to enhance polar pathway transport, especially of

hydrophilic drugs.The ability of a surfactant to alter penetration is a function of the polar
head group and the hydrocarbon chain length.
Anionic Surfactants: e.g. Dioctyl sulphosuccinate, Sodium lauryl sulphate,

Decodecylmethyl sulphoxide etc.
Nonionic Surfactants: e.g. Pluronic F127, Pluronic F68, etc.
BileSalts: e.g. Sodium ms taurocholate, Sodium deoxycholate,

Sodium tauroglycocholate.
Biary system: These systems apparently open up the heterogeneous multilaminate

pathway as well as the continuous pathways.e.g. Propylene glycol-oleic acid and 1, 4-
butane diol-linoleic acid.
c) Miscellaneous chemicals
These include urea, a hydrating and keratolytic agent; N, N-dimethyl-m-toluamide;

calcium thioglycolate; anticholinergic agents.
Some potential permeation enhancers have recently been described but the available data
on their effectiveness sparse. These include eucalyptol, di-o-methyl-ß-cyclodextrin and
soyabeancasei
4.Other Excipients
a) Adhesives:
The fastening of all transdermal devices to the skin has so far been done by
usinga pressure sensitive adhesive which can be positioned on the face of the
device or in the back of the device and extending peripherally. Both adhesive
systems should fulfill the following criteria
(i)Should adhere to the skin aggressively, should be easily removed.

(ii)Should not leave an unwashable residue on the skin.
(iii) Should not irritate or sensitize the skin.The face adhesive system should also fulfill
the following criteria.
(i)Physical and chemical compatibility with the drug, excipients and enhancers
of the device of which it is a part.
(ii) Permeation of drug should not be affected.
(iii) The delivery of simple or blended permeation enhancers should not

be affected.
b) Backing membrane:
Backing membranes are flexible and they provide a good bond to the drug reservoir,
prevent drug from leaving the dosage form through the top, and accept printing. It is
impermeable substance that protects the product during use on the skin e.g. metallic
plastic laminate, plastic backing with absorbent pad and occlusive base plate (aluminium
foil), adhesive foam pad (flexible polyurethane) with occlusive base plate (aluminium foil
disc)
Factors Considered:
• Drug delivery system
• Drug formulation and consistency
• Bioavailability
• Testing and quality assurance
Drug Delivery System

 Each TDS is optimized to deliver the drug at desired rate into systemic
circulation. The components are selected based on physicochemical and
pharmacological properties of the drug to optimize the drug penetration rate.
 Variability in the component mixture or manufacturing process maynot ensure
adequate biopharmceutics quality of the product.
 Appropriate quality control measures and stability of the formulation are
essential to ensure dosing accuracy and reproducibility
Bioavailability
 The appropriate biopharmaceutical properties of the TDS is most vital to deliver

the drug at optimized rate for therapeutic effectiveness of the drug product.
 Lower rates of delivery may result in ineffective drug concentrations, and higher
rates of delivery may result in toxic and adverse reactions.
 The optimized formulation with adequate adhesive properties at the site of
application are important to assure reproducible bioavailability and drug
effectiveness
Testing and Quality Assurance
 The product must be tested for its potency, content uniformity, purity, residual
solvents, residual monomers, release liner peel force, adhesion, microbial testing,
release rate and pouch integrity to ensure product performance
Drug Formulation and Consistency
 The adhesive selected should provide good skin contact over the total area of
application for entire duration to ensure adequate drug delivery.
 Interactions with all components including skin irritation and sensitization
need to be evaluated to ensure dosing accuracy and reproductivity.

PENETRATION ENHANCEMENT THROUGH OPTIMIZATION OF

DRUG AND VEHICLE PROPERTIES.
Drug permeation across the stratum corneum obeysFick’s first law (equation 1) where
steady-state flux (J) isrelated to the diffusion coefficient (D) of the drug in thestratum
corneum over a diffusional path length or membranethickness (h), the partition
coefficient (P) between theTechniques to optimise drug permeation across the
skin.stratum corneum and the vehicle, and the applied drug
concentration (C0) which is assumed to be constant:
h
DC P
J
dt
dm 
 0 (1)Equation 1 aids in identifying the ideal parameters drug
diffusion across the skin. The influence of solubilityand partition coefficient of a drug on
diffusion across thestratum corneum has been extensively studied and anexcellent review
of the work was published by Katz and Poulsen . Molecules showing intermediate
partitioncoefficients (log Poctanol/water of 1-3) have adequate solubilitywithin the lipid
domains of the stratum corneum to permithydrophilic nature to allow partitioning into the
viabletissues diffusion through this domain whilst still having sufficient
of the epidermis.

Fig…Diagrammatic representation of the stratum corneum and the intercellular

and transcellular routes of penetration

relationship was obtained between skin permeability and partition coefficient for a series
of salicylates and non steroidalanti-inflammatory drugs. The maximum permeability
measurement being attained at log P value 2.5,which is typical of these types of
experiments. Optimal permeability has been shown to be related to low molecular size
(ideally less than 500 Da as this affects diffusion coefficient, and low melting point
which is related to solubility. When a drug possesses these ideal characteristics (as in the
case of nicotine and nitroglycerin),transdermal delivery is feasible. However, where a
drug does not possess ideal physicochemical properties, manipulation of the drug or
vehicle to enhance diffusion, becomes necessary. The approaches that have been
investigated are summarised in and discussed below.1. Prodrugs and Ion-Pairs The
prodrug approach has been investigated to enhancedermal and transdermal delivery of
drugs with unfavourable partition coefficients]. The prodrug design strategygenerally
involves addition of a promoiety to increase partition coefficient and hence solubility and
transport of theparent drug in the stratum corneum. Upon reaching theviable epidermis,
esterases release the parent drug byhydrolysis thereby optimising solubility in the
aqueous epidermis. The intrinsic poor permeability of the very polar6-mercaptopurine
was increased up to 240 times using S6-acyloxymethyl and 9-dialkylaminomethyl
promoieties ]and that of 5-fluorouracil, a polar drug with reasonable skinpermeability

was increased up to 25 times by forming N-acylderivatives.The prodrug approach has

also beeninvestigated for increasing skin permeability of non-steroidalanti-inflammatory
drugs naltrexone nalbuphine buprenorphine .b-blockers and other drugs Well established
commercial preparations using this approach include steroid esters (e.g.betamethasone-
17-valerate), which provide greater topicalanti-inflammatory activity than the parent
steroids.Charged drug molecules do not readily partition into orpermeate through human
skin. Formation of lipophilic ionpairshas been investigated to increase stratum
corneumpenetration of charged species. This strategy involves addingan oppositely
charged species to the charged drug, formingan ion-pair in which the charges are
neutralised so that thecomplex can partition into and permeate through the stratum
corneum. The ion-pair then dissociates in the aqueous viableepidermis releasing the
parent charged drug which candiffuse within the epidermal and dermal tissues. Ingeneral
permeability increases of only two to three-fold havebeen obtained although Sarveiya et
al. recently reporteda 16-fold increase in the steady-state flux of ibuprofen ionpairsacross
a lipophilic membrane.
1.Chemical Potential of Drug in Vehicle –
Saturated and Supersaturated Solutions The maximum skin penetration rate is obtained
when a drug isat its highest thermodynamic activity as is the case ina supersaturated
solution. This can be demonstrated based on.
Equation 1 rewritten in terms of thermodynamic activities
[50]:
h
aD
dt
dm
(2)
Where is the thermodynamic activity of the permeantin its vehicle and is the
effective activity coefficient in themembrane. This dependence on thermodynamic
activityrather than concentration was elegantly demonstrated byTwist and Zatz .The
diffusion through a siliconemembrane of saturated solutions of parabens in

elevendifferent solvents was determined. Due to the different solubility of the parabens in
the various solvents, theconcentration varied over two orders of magnitude.However,
paraben flux was the same from all solvents, as thethermodynamic activity remained
constant because saturatedconditions were maintained throughout the
experiment.Supersaturated solutions can occur due to evaporation ofsolvent or by mixing
of cosolvents. Clinically, the mostcommon mechanism is evaporation of solvent from
thewarm skin surface which probably occurs in many topicallyapplied formulations. In
addition, if water is imbibed fromthe skin into the vehicle and acts as an antisolvent,
thethermodynamic activity of the permeant would increase .Increases in drug flux of five-
to ten-fold have been reportedfrom supersaturated solutions of a number of drugs.These
systems are inherently unstable and require theincorporation of antinucleating agents to
improve stability.Magreb et al reported that the flux of oestradiol from an18-times
saturation system was increased 18-fold acrosshuman membrane but only 13-fold in
silastic membrane.They suggested that the complex mixture of fatty acids,cholesterol,
ceramides, etc. in the stratum corneum mayprovide an antinucleating effect thereby
stabilizing thesupersaturated system.
2. Eutectic Systems
As previously described, the melting point of a druginfluences solubility and hence skin
penetration. Accordingto regular solution theory, the lower the melting point, thegreater
the solubility of a material in a given solvent,including skin lipids. The melting point of a
drug deliverysystem can be lowered by formation of a eutectic mixture: amixture of two
components which, at a certain ratio, inhibitthe crystalline process of each other, such
that the meltingpoint of the two components in the mixture is less than thatof each
component alone. EMLA cream, a formulationconsisting of a eutectic mixture of
lignocaine and prilocaineapplied under an occlusive film, provides effective
localanaesthesia for pain-free venepuncture and other procedures. The 1:1 eutectic
mixture (m.p. 18°C) is an oil which isformulated as an oil-in-water emulsion thereby
maximizingthe thermodynamic activity of the local anaesthetics. Anumber of eutectic
systems containing a penetrationenhancer as the second component have been reported,
forexample: ibuprofen with terpenes ,menthol andmethyl nicotinate; propranolol with
fatty acids ;andlignocaine with menthol .In all cases, the melting pointof the drug was

depressed to around or below skintemperature thereby enhancing drug solubility.

However, itis also likely that the interaction of the penetration enhancerwith stratum
corneum lipids also contributed to the increaseddrug flux.
3. Complexes
Complexation of drugs with cyclodextrins has been usedto enhance aqueous solubility
and drug stability.Cyclodextrins of pharmaceutical relevance contain 6, 7 or 8dextrose
molecules ( -, -, -cyclodextrin) bound in a 1,4-configuration to form rings of
various diameters. The ringhas a hydrophilic exterior and lipophilic core in
whichappropriately sized organic molecules can form non-covalentinclusion complexes
resulting in increased aqueous solubilityand chemical stability. Derivatives of -
cyclodextrinwith increased water solubility (e.g. hydroxypropyl- -cyclodextrin HP-
-CD) are most commonly used inpharmaceutical formulation. Cyclodextrin
complexes havebeen shown to increase the stability, wettability anddissolution of the
lipophilic insect repellent N,N-diethyl-mtoluamideDEET) and the stability and
photostability ofsunscreens . Cyclodextrins are large molecules, withmolecular weights
greater than 1000 Da, therefore it wouldbe expected that they would not readily permeate
the skin.Complexation with cyclodextrins has been variouslyreported to both increase
and decrease skinpenetration. In a recent review of the availabledata, Loftsson and
Masson concluded that the effect on skinpenetration may be related to cyclodextrin
concentration,with reduced flux generally observed at relatively highcyclodextrin
concentrations, whilst low cyclodextrinconcentrations resulting in increased flux .As flux
isproportional to the free drug concentration, where thecyclodextrin concentration is
sufficient to complex only thedrug which is in excess of its solubility, an increase in
fluxmight be expected. However, at higher cyclodextrinconcentrations, the excess
cyclodextrin would be expected tocomplex free drug and hence reduce flux. Skin
penetrationenhancement has also been attributed to extraction of stratumcorneum lipids
by cyclodextrins. Given that mostexperiments that have reported cyclodextrin mediated
fluxenhancement have used rodent model membranes in whichlipid extraction is
considerably easier than human skin,the penetration enhancement of cyclodextrin
complexationmay be an overestimate. Shaker and colleagues recentlyconcluded that

complexation with HP- -CD had no effect onthe flux of cortisone through hairless
mouse skin by either ofthe proposed mechanisms .This remains a controversialarea.
4. Liposomes and Vesicles.
There are many examples of cosmetic products in whichthe active ingredients are
encapsulated in vesicles. Theseinclude humectants such as glycerol and urea,
sunscreeningand tanning agents, enzymes, etc. Although there are fewcommercial topical
products containing encapsulated drugs,there is a considerable body of research in the
topic. Avariety of encapsulating systems have been evaluatedincluding liposomes,
deformable liposomes or transfersomes,ethosomes and niosomes.Liposomes are colloidal
particles formed as concentricbiomolecular layers that are capable of encapsulating
drugs.Their potential for delivering drugs to the skin was firstreported by Mezei and
Gulasekharam in 1980 who showedthat the skin delivery of triamcinolone acetonide was
four tofive times greater from a liposomal lotion than an ointmentcontaining the same
drug concentration..Phosphatidylcholine from soybean or egg yolk is the mostcommon
composition although many other potentialingredients have been evaluated .Cholesterol
added tothe composition tends to stabilize the structure therebygenerating more rigid
liposomes. Recent studies have tendedto be focused on delivery of macromolecules such
asinterferon , gene delivery and cutaneous vaccination, in some cases combining the
liposomal delivery systemwith other physical enhancement techniques such
aselectroporation . Their delivery mechanism is reported tobe associated with
accumulation of the liposomes andassociated drug in the stratum corneum and upper
skilayers, with minimal drug penetrating to the deeper tissues
and systemic circulation (eg.. The mechanism ofenhanced drug uptake into the stratum
corneum is unclear. Itis possible that the liposomes either penetrate the stratumcorneum
to some extent then interact with the skin lipids torelease their drug or that only their
components enter thestratum corneum. It is interesting that the most effectiveliposomes
are reported to be those composed of lipidssimilar to stratum corneum lipids , which are
likely tomost readily enter stratum corneum lipid lamellae and fusewith endogenous
lipids.Transfersomes are vesicles composed of phospholipids astheir main ingredient with
10-25% surfactant (such assodium cholate) and 3-10% ethanol. The surfactantmolecules
act as “edge activators”, conferringultradeformability on the transfersomes, which

reportedlyallows them to squeeze through channels in the stratumcorneum that are less
than one-tenth the diameter of thetransfersome . According to their inventors,
whereliposomes are too large to pass through pores of less than 50nm in size,
transfersomes up to 500 nm can squeeze throughto penetrate the stratum corneum barrier
spontaneously . They suggest that the driving force for penetration intothe skin is the
“transdermal gradient” caused by thedifference in water content between the relatively
dehydratedskin surface (approximately 20% water) and the aqueousviable epidermis
(close to 100%). A lipid suspension placedon a non-occluded skin surface is subject to
evaporation, andto avoid dehydration transfersomes must penetrate to deepertissues.
Conventional liposomes remain near the skinsurface, dehydrate and fuse, whilst
deformable transfersomespenetrate via the pores in the stratum corneum and follow
thehydration gradient. Extraordinary claims are made for the
penetration enhancement ability of transfersomes, such asskin transport of 50-80% of the
applied dose oftransferosome-associated insulin . More recently Guo etal. also
demonstrated that flexible lecithin liposomescontaining insulin applied to mouse skin
causedhypoglycaemia, whilst conventional liposomes and insulinsolution had no
hypoglycaemic effect . Other researcherswho have evaluated transfersomes have also
shown thatultradeformable liposomes are superior to rigid liposomes.For example, in a
series of studies the skin penetration ofestradiol was enhanced more by ultradeformable
liposomalformulation (17-fold) than by traditional liposomes (9-fold).Pretreatment of the
skin membranes with emptvesicles had minimal effect on drug flux and the size of
thevesicles did not influence the enhancement effect. This groupalso confirmed that
hydration gradient was the main drivingforce for transport of highly deformable
liposomes as the 17-fold increase in oestradiol flux reduced to a six to nine-foldincrease
under occlusion . Evidence of vesicles betweenthe corneocytes in the outer layers of the
stratum corneumhas been demonstrated by electron and fluorescencemicroscopy . Whilst
the mechanism and degree ofenhancement of deformable liposomes remains
controversialit is likely that this formulation approach will receive
furtherattention.Ethosomes are liposomes with a high alcohol contentcapable of
enhancing penetration to deep tissues and thesystemic circulation . It is proposed that
thealcohol fluidises the ethosomal lipids and stratum corneumbilayer lipids thus allowing

the soft, malleable ethosomes topenetrate. Niosomes are vesicles composed of

nonionicsurfactants that have been evaluated as carriers for a numberof drug and
cosmetic applications . This areacontinues to develop with further evaluation of
currentformulations and reports of other vesicle forming materials.
KINETICS OF TRANSDERMAL PERMEATION
Knowledge of skin permeation kinetics is vital to the successful development

of transdermal therapeutic systems. Transdermal permeation of a drug involves
the following steps:
1. Sorption by stratum corneum.
2. Penetration of drug through viable

epidermis.
3. Uptake of the drug by the capillary

network in the dermal papillary layer.
This permeation can be possible only if the drug possesses certain physiochemical
properties.The rate of permeation across the skin is given by:
dQ
------ = P s ( C d – Cr ) .. ……………………….. (1)
dt
where Cd and Cr are the concentration of the skin penetrant

in the donor compartment i.e. on the surface of stratum corneum and in the receptor
compartment i.e. body respectively. Ps is the overall permeability coefficient

of the skin tissue to the penetrant. This permeability coefficient is given

by the relationship:
Ks
Dss
Ps = ---------------------
Hs
where Ks is the partition coefficient for the interfacial

partitioning of the penetrant molecule from a solution medium or a transdermal
therapeutic system on to the stratum corneum, Dss is the apparent
diffusivity for the steady state diffusion of the penetrant molecule through
a thickness of skin tissues and hs is the overall thickness of skin
tissues. As Ks ,Dss and hs are constant under
given conditions the permeability coefficient Ps for a skin penetrant
can be considered to be constant. From equation (1) it is clear that a constant
rate of drug permeation can be obtained only when Cd >> Cr
i.e. the drug concentration at the surface of the stratum corneum Cd
is consistently and substantially greater than the drug concentration in the
body Cr. The equation becomes:
dQ
------- = P s Cd
dt
And the rate of skin permeation is constant provided the magnitude of Cd

remains fairly constant throughout the course of skin permeation. For keeping
Cd constant the drug should be released from the device at a rate
Rr i.e. either constant or greater than the rate of skin uptake Ra

i.e
. Rr >> Ra .
Since Rr >> Ra , the drug concentration on the

skin surface Cd is maintained at a level equal to or greater than
the equilibrium solubility of the drug in the stratum corneum Cs
.i.e. Cd>>Cs. Therefore a maximum rate of skin permeation
is obtained and is given by the equation:
(dQ/dt)m = PsCs
From the above equation it can be seen that the maximum rate of
skin permeation depends upon the skin permeability coefficient Ps
and is equilibrium solubility in the stratum corneum C s. Thus skin
permeation appears to be stratum corneum limited. (8)
Evaluation.
Cadaver skin permeation testing helps determine the feasibility of a compound to be

incorporated into a transdermal drug delivery system.
Schizophrenia has been one of the major diseases afflicting mankind in today's scenario.
Haloperidol lactate, an antipsychotic drug, is supposed to be effective in the treatment of
chronic schizophrenic patients. Evidence of first-pass metabolism of this drug and
prolonged duration of treatment required for this particular disorder offer a major
challenge in its treatment by conventional route. Long-acting preparations of these drugs
may be helpful. Thus the haloperidol lactate-loaded transdermal drug delivery system
(TDDS) improved bioavailability and hence is a better alternative during the prolonged
period of psychiatric treatment.

Haloperidol belongs to the phenothiazine group of drugs. It produces two main kinds of
motor disturbances in humans, namely, Parkinson's disease-like symptoms and tardive
dyskinesia. Haloperidol is a widely used neuroleptic, administered as intramuscular depot
injection or used orally to suppress psychiatric disorders. The Parkinson's disease caused
by haloperidol is of great concern for psychiatrists all over the world.
The low-dose haloperidol maintenance therapy is required to control the psychotic

symptoms, and long-term prophylactic treatment is needed to prevent relapses. Long-
acting modified dosage forms of haloperidol are effective in patients and can help to
address the problem of poor patient compliance. The use of this drug in the lowest
possible effective dosage is recommended for minimizing the risk of major side effects.
Based on these hypotheses, a modified transdermal drug delivery system was developed.
Simple drug-matrix dispersion type of transdermal drug delivery system for haloperidol
was designed for prolonged period of maintenance therapy instead of convention oral
dosage forms. Moreover, the physicochemical characteristics of haloperidol also comply
with the general requirement for designing a TDDS to a good extent.
This search and investigation is expected to add extensively to the existing knowledge
and information in the field of proper drug regimen and maintenance therapy of
schizophrenia with controlled-release TDDS of haloperidol.
Material & method
Ethyl cellulose was supplied by S. P. Pharmaceuticals, USA. Polyvinyl pyrrolidone

(PVP) K-30 was obtained from S. D. Fine Chemicals, Mumbai, India. Dibutyl phthalate
was procured from Central Drug House Ltd., New Delhi. Chloroform was obtained
commercially from Ranbaxy Fine Chemicals, New Delhi. Hyaluronidase was obtained
from Charles Pharma Ltd. Polyethylene glycol 400 and sodium chloride were purchased
from S. D. Fine Chemicals, Mumbai. Haloperidol lactate was received as a gift sample
from Torrent Pharmaceuticals, Ahmedabad.

Preparationoftransdermalpatches
TDDSs composed of different ratios of EC- and PVP-containing haloperidol lactate (6

mg/cm 2 ) was casted on enumbra Petri dish by solvent-evaporation technique. Dibutyl
phthalate [ 3] was incorporated as a plasticizer at concentration of 30% w/w of dry weight
of polymer, and 4% of hyaluronidase was incorporated as a permeation enhancer.
Backing membrane was cast by pouring and then evaporating 4% aqueous solution of
polyvinyl alcohol in Petri dish at 60°C for 6 h. The matrix was prepared by pouring the
homogenous dispersion of drug with different blends of EC with PVP in chloroform on
the backing membrane in Petri dish. [ 4] The above dispersion was evaporated slowly at
40°C for 2 h to achieve a drug polymer matrix patch. The dry patches were kept in
desiccatorsuntiluse.
Preparationofbarriers:Humancadaverskin
The fresh, full-thickness (75-80 µm) human cadaver skin (of thigh region) of both sexes
and age group 20 to 45 years was obtained from the Postmortem Department of Forensic
Medicine, Victoria Hospital. The skin was immersed in water at 60°C for a period of 5
min. The epidermis was peeled from the dermis after exposure. The isolated epidermis
[ 5]
(25 ± 5 µm) was rapidly rinsed with hexane to remove surface lipids, rinsed with
water, and then either used or stored frozen (for not more than 48 h) wrapped in
aluminum foil.
Solubilitymeasurement
Solubility of haloperidol lactate was determined at several values of pH, viz., 4.0, 5.0,
6.8, 7.4, 8.0, and 9.0. Excess of haloperidol lactate was added to 10 mL of phosphate
buffer solutions. At each level, the samples were stirred in a conical flask for 24 h at
37°C. The pH of the samples was checked and adjusted with 0.1-M perchloric acid
whenever necessary. The suspensions were filtered using a 0.45-micron Whatman filter

paper. The concentration of haloperidol lactate in the filtrate was determined

spectrophotometrically by measuring at 245 nm.
Partitioncoefficientodruginoctanol/watersystem
The partition coefficient of the drug was determined by taking equal volumes of 1-
octanol and aqueous solution in a separating funnel. In case of water-soluble drugs, a drug
solution of 25 µg/mL was prepared in distilled water; and in case of water-insoluble
drugs, a drug solution of 25 µg/mL was prepared in 1-octanol. Twenty-five milliliters of
this solution was taken in a separating funnel and shaken with equal volume of 1-
octanol/water system for 30 min and allowed to stand for 1 h. The mixture was then
centrifuged at 2000 rpm for 10 min, and concentration of drug in each phase was
determined spectrophotometrically by measuring absorbance at 245 nm. The partition
coefficient (Kp) was calculated from the equation.
Permeability coefficient (P):
Permeability coefficient is the velocity of drug passage through the membrane in µg/cm 2
/h. The permeability coefficient was calculated from the slope of the graph of percentage
of drug transported versus time as,
P = slope x Vd/S ..........................................(2)
where Vd = volume of donor solution;

S = surface area of tissue.
Flux ( J): Flux is defined as the amount of material flowing through a unit cross-

sectional barrier in unit time. It is calculated by
Flux (J) = P x CD .........................................(3)
where CD = concentration of donor solution;

P = permeability.
Enhancement ratio: Enhancement ratio was used to evaluate the effect of permeation
enhancer on diffusion and permeation of selected drug molecules. It is calculated by,
SpectrophotometerUV/VISanalysis
Haloperidol lactate was determined using Shimadzu UV spectrophotometer at 245 nm. [ 11]
A correlation coefficient of 0.9999 was obtained with a slope value of 0.0351.
Drug-excipientinteractionstudy
FT-IR spectra of haloperidol lactate, ethyl cellulose, PVP, transdermal film loaded with
drug, and adjuvants were taken using Perkin-Elmer FT-IR spectrophotometer (model
1600- KBr disk method). Fifty milligrams of sample and 150 mg of KBr was taken in a
mortar and triturated
Scanningelectronmicroscopy
The external morphology of the transdermal patch was analyzed using a scanning
electron microscope (JMS 6100 JEOL, Tokyo, Japan). The samples placed on the stubs

were coated finally with gold palladium and examined under the Microscope and shown
in
Differentialscanningcalorimetry
The thermograms of pure and prepared patches was scanned using ifferential scanning
calorimetry. The samples were hermetically sealed in flat-bottomed aluminum pans and
heated over a temperature range of 40°C to 240°C at a rate of 10°K/min using alumina as
a reference standard.
Evaluationoftransdermalpatches
Thicknessdetermination
The aim of the present study was to check the uniformity of thickness of the formulated
films. The thickness was measured at five different points of the film. Using BAKER
Digital caliper, the average of five readings was calculated.
Uniformityofweight
Five different patches from individual batches were weighed individually, and the
average weight was calculated; the individual weight should not deviate significantly
from the average weight. The tests were performed on films which were dried at 60°C for
4 h prior to testing.
Moisturecontent
The film was weighed and kept in a desiccator containing calcium chloride at 40°C and
dried for at least 24 h. The film was weighed until it showed a constant weight. The
moisture content was the difference between the constant weight taken and the initial
weight and was reported in terms of percentage (by weight) moisture content
Flatnessandelongationbrake
Longitudinal strips were cut out from the prepared medicated film. The flatness was
determined at various points by using vernier calipers calculated. The percentage
elongation brake was determined by noting the length just before the break point and
substituted in the formula no 5.
where L 1 = final length of each strip; and L 2 = initial length of each strip.
Moistureuptake
A weighed film kept in a dessicator at 40°C for 24 h was taken out and exposed to
relative humidities of 75% (saturated solution of sodium chloride) and 93% (saturated
solution of ammonium hydrogen phosphate) respectively, at room temperature. Then the
films were measured periodically to constant weights.
Determinationoftensilestrength
Tensile strength was determined by using computerized Precisa bottom-loading balance,

with necessary modifications. A 1 x 1-cm patch was taken and subjected to studies.
Drugcontentdeterminationoffilm
Four pieces of 1 cm 2 each (1 x 1 cm) were cut from different parts of the film. Each was
taken in separate stoppered conical flasks containing 100 mL of suitable dissolution
medium (0.1-N HCL:methanol mixture) and stirred vigorously for 6 h using magnetic
stirrer. The above solutions were filtered and suitable dilutions were made. Absorbances
were observed using Shimadzu 160A UV-Visible recording spectrophotometer at their

respective wavelengths, against a blank solution which was prepared by the same
protocol but not containing drug.
Invitrodiffusionstudy
Franz diffusion cell was used for the study of in vitro release patterns of the prepared
TDDS formulations. The elution mediums of 20% PEG 400 in normal saline, and
epidermis of the fresh human cadaver skin excised from the thigh portion were used as
the barrier. The films were placed in between the donor and receptor compartments in
such a way that the drug-releasing surface faced the receptor compartment. The receptor
compartment was filled with the elution medium, and a small bar magnet was used to stir
the medium at a speed of 60 rpm with the help of a magnetic stirrer. The temperature of
the elution medium was maintained and controlled at 37°C ± 1°C by a thermostatic
arrangement. An aliquot of 1 mL withdrawn at predetermined intervals, being replenished
by equal volumes of the elution medium, withdrawal of samples was carried out for a
period of 24 h. The drug concentration in the aliquot was determined
spectrophotometrically and was calculated with the help of a standard calibration curve.
Dataanalysis
The pharmaceutical dosage forms that do not disaggregate and release the drug slowly
(assuming that area does not change and no equilibrium conditions are obtained) could be
represented by a zero-order kinetic equation. Hixson and Crowell (1931) recognized that
the particle regular area is proportional to the cubic root of its volume. Colombo et al.
suggested that the quantity of drug from the matrix-type delivery system is often
analyzed as a function of the square root of time, which is typical for a system where
drug release is governed by pure diffusion. However, this relationship in a transdermal
system is not justified completely as such systems can be erodible. Therefore, analysis of
drug release from transdermal system must be performed with a flexible model that can
identify the contribution to overall kinetics. Dissolution data was treated with different
releasekineticequations.

Zero-orderreleaseequation
Q = k 0 t ...........................................(6)
Higuchi's square root of time equation
1/2
Q = k H t ....................................(7)
First-order release equation
Log Q t = LogQ 0 + Kt/2.303 ........(8)
Korsmeyer-Peppas equation
n
F = (M t /M) = K m t .......................(9)
where Q is the amount of drug release at time t; M t is drug release at time t; M is the total
amount of drug in dosage form; F is fraction of drug release at time t; K 0 is zero-order
release rate constant; K H is Higuchi square root of time release rate constant; K m is a
constant dependent on geometry of dosage form; and n is diffusion exponent indicating
the mechanism of drug release. If the cylinder value of n is 0.5, it indicates fickian
diffusion; if between 0.5 and 1.0, anomalous transport; 1.0 indicates case-II transport; and
higher than 1.0, super case-II transport
Results and Discussion:-
The matrix-type transdermal films of haloperidol lactate were prepared by solvent-

evaporation technique using combination of hydrophilic and lipophilic polymers. PVP is
added to an insoluble film former, EC, that tends to increase its release rate. The resultant
can be contributed to the leaching of soluble component, which leads to the formation of
pores and then decrease in the mean diffusion path length of the drug molecules. PVP
acts as a nucleating agent that retards the crystallization of the drug and enhances the

solubility of the drug in the matrix by sustaining it in an amorphous form.

Partition coefficient of haloperidol lactate, in octanol/water system was found to be
1.248. Solubility and permeability of haloperidol lactate were evaluated at various values
of pH of phosphate buffer. It was seen that solubility decreases with increase in the pH of
phosphate buffer, and the permeability coefficient increases with increase in the value of
pH.
The permeability studies of haloperidol lactate in a modified Franz diffusion cell through
the human cadaver skin showed that the permeability coefficient (P) and flux of
haloperidol lactate were 15.96 m/h and 95.76 µg/cm 2 /h respectively. The enhancement
ratios of drug with different enhancers were evaluated using modified Franz diffusion cell
through human cadaver skin. The permeability coefficient, flux, and enhancement ratio of
drug with IPM were found to be 15.45 cm/h, 92.7 µg/cm 2 /h, and 0.986 respectively; and
with hyaluronidase, these were found to be 34.18 cm/h, 205.08 µg/cm 2 /h, and 2.141
respectively.
CONCLUSION
Transdermal drug delivery is hardly an old technology, and the technology no

longer is just adhesive patches. Due to the recent advances in technology and
the incorporation of the drug to the site of action without rupturing the skin
membrane transdermal route is becoming the most widely accepted route of drug
administration. It promises to eliminate needles for administration of a wide
variety of drugs in the future.The search for the ideal skin penetration enhancer has been
the focus of considerable research effort over a number of decades. Although many
potent enhancers have been in most cases their enhancement effects are associated with
toxicity, therefore limiting their clinical application. In recent years the use of a number
of biophysical techniques has aided in our understanding of the nature of the stratum corn
eum barrier and the way in which chemicals interact with and influence this structure. A
better understanding of the interaction of enhancers with the stra tum corneum and the
development of structure activity relationships for enhancers will aid in the design
ofenhancers with optimal characteristics and minimal toxicity.

REFERENCES:-
 Chien, YW, Novel drug delivery systems, Drugs and the Pharmaceutical Sciences,
Vol.50, Marcel Dekker, New York, NY;1992;797
 Roberts MS, Targeted drug delivery to the skin and deeper tissues: role of
physiology, solute structure and disease.Clin Exp Pharmacol Physiol 1997
Nov;24(11):874-9.
 Aulton.M.E, Pharmaceutics; The science of dosage form design, second edition,
Churchill Livingston, Harcourt publishers-2002.
 Ansel.H.C, Loyd.A.V, Popovich.N.G, Pharmaceutical dosage forms and drug
delivery systems, Seventh edition, Lippincots and Willkins publication.
 Brahmankar.D.M, Jaiswal.S.B, Biopharmaceutics and pharmacokinetics A
Teatise. Vallabh Prakashan, Delhi1995,335-371.
 Banker, G. S and Rhodes, C. T Modern pharmaceutics, third edition, New York,
Marcel Dekker, inc,. 1990.
 Jain.N.K, Controlled and novel drug delivery ,first edition, CBS publishers and
distributors, New Delhi.1997.
 Mathiowitz.Z.E, Chickering.D.E, Lehr.C.M, Bioadhesive drug delivery systems;
fundamentals,novel approaches and development, Marcel Dekker, inc New York .
Basel
 www.Controlled release drug delivery systems.com

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TRANSDERMAL DRUG DELIVERY SYSTEM

RKDF COLLEGE OF PHARMACY Page 1

drugs across this layer. The method to circumvent this is to engineer

• Liquid Reservoir Patch

Drug in solution or suspension between the backing layer and a rate

• Drug in Adhesive Patch

Drug dispersed in adhesive, in direct contact with skin

• Polymer Matrix Patch

Drug in solution or suspension dispersed within a polymer

• Multi-laminate Matrix Patch

Drug dispersed in adhesive in multi-layers separated by membranes.

TYPES OF TRANSDERMAL PATCHES

Four Major Transdermal Systems

RKDF COLLEGE OF PHARMACY Page 2

The Single-layer Drug-in-Adhesive system is characterized by the inclusion of

RKDF COLLEGE OF PHARMACY Page 3

RKDF COLLEGE OF PHARMACY Page 4

The Multi-layer Drug-in-Adhesive is similar to the Single-layer Drug-in-Adhesive

The rate of drug release in this system is defined by:

where Ka/r is the partition coefficient for the interfacial partitioning

RKDF COLLEGE OF PHARMACY Page 5

The Reservoir transdermal system design is characterized by the inclusion

RKDF COLLEGE OF PHARMACY Page 6

The Matrix system design is characterized by the inclusion of a semisolid

RKDF COLLEGE OF PHARMACY Page 7

The rate of drug release from this type of system is defined as :

The components of transdermal devices

1. Polymer matrix or matrices.

RKDF COLLEGE OF PHARMACY Page 8

e.g. Polybutadieine, Hydrin rubber, Polysiloxane, Silicone rubber, Nitrile, Acrylonitrile,

e.g. Polyvinyl alcohol, Polyvinyl chloride, Polyethylene, Polypropylene, Polyacrylate,

RKDF COLLEGE OF PHARMACY Page 9

For successfully developing a transdermal drug delivery system,

3. The drug should have low melting point

These are compounds which promote skin permeability by altering

RKDF COLLEGE OF PHARMACY Page 10

These compounds are proposed to enhance polar pathway transport, especially of

Anionic Surfactants: e.g. Dioctyl sulphosuccinate, Sodium lauryl sulphate,

Nonionic Surfactants: e.g. Pluronic F127, Pluronic F68, etc.

BileSalts: e.g. Sodium ms taurocholate, Sodium deoxycholate,

Biary system: These systems apparently open up the heterogeneous multilaminate

These include urea, a hydrating and keratolytic agent; N, N-dimethyl-m-toluamide;

(i)Should adhere to the skin aggressively, should be easily removed.

RKDF COLLEGE OF PHARMACY Page 11

(ii)Should not leave an unwashable residue on the skin.

(ii) Permeation of drug should not be affected.

(iii) The delivery of simple or blended permeation enhancers should not

• Drug delivery system

• Drug formulation and consistency

• Testing and quality assurance

Drug Delivery System

RKDF COLLEGE OF PHARMACY Page 12

 The appropriate biopharmaceutical properties of the TDS is most vital to deliver

Testing and Quality Assurance

Drug Formulation and Consistency

RKDF COLLEGE OF PHARMACY Page 13

PENETRATION ENHANCEMENT THROUGH OPTIMIZATION OF

RKDF COLLEGE OF PHARMACY Page 14

Fig…Diagrammatic representation of the stratum corneum and the intercellular

RKDF COLLEGE OF PHARMACY Page 15

RKDF COLLEGE OF PHARMACY Page 16

was increased up to 25 times by forming N-acylderivatives.The prodrug approach has

RKDF COLLEGE OF PHARMACY Page 17