Top Banner
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 RKDF COLLEGE OF PHARMACY Page 1
51
Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Page 1: 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

Page 2: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

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 

RKDF COLLEGE OF PHARMACY Page 2

Page 3: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

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.

RKDF COLLEGE OF PHARMACY Page 3

Page 4: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

                    

 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 

RKDF COLLEGE OF PHARMACY Page 4

Page 5: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

                   

 

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)

RKDF COLLEGE OF PHARMACY Page 5

Page 6: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

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 )

RKDF COLLEGE OF PHARMACY Page 6

Page 7: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

                                          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.

RKDF COLLEGE OF PHARMACY Page 7

Page 8: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

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

 

                dQ                            ACp Dp     ½

                        ------                        =               ----------------

                 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.

RKDF COLLEGE OF PHARMACY Page 8

Page 9: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

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

RKDF COLLEGE OF PHARMACY Page 9

Page 10: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

 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

RKDF COLLEGE OF PHARMACY Page 10

Page 11: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

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.

RKDF COLLEGE OF PHARMACY Page 11

Page 12: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

(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

RKDF COLLEGE OF PHARMACY Page 12

Page 13: Trans Dermal Drug Delivery

TRANSDERMAL 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.

RKDF COLLEGE OF PHARMACY Page 13

Page 14: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

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.

RKDF COLLEGE OF PHARMACY Page 14

Page 15: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

Fig…Diagrammatic representation of the stratum corneum and the intercellular

and transcellular routes of penetration

RKDF COLLEGE OF PHARMACY Page 15

Page 16: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

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

RKDF COLLEGE OF PHARMACY Page 16

Page 17: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

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

RKDF COLLEGE OF PHARMACY Page 17

Page 18: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

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

RKDF COLLEGE OF PHARMACY Page 18

Page 19: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

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

RKDF COLLEGE OF PHARMACY Page 19

Page 20: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

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

RKDF COLLEGE OF PHARMACY Page 20

Page 21: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

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

RKDF COLLEGE OF PHARMACY Page 21

Page 22: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

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   

  ------    =       Ps ( Cd – 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

RKDF COLLEGE OF PHARMACY Page 22

Page 23: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

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

-------     =      Ps 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

RKDF COLLEGE OF PHARMACY Page 23

Page 24: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

             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 Cs. 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.

RKDF COLLEGE OF PHARMACY Page 24

Page 25: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

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

RKDF COLLEGE OF PHARMACY Page 25

Page 26: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

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

(25 ± 5 µm) was rapidly rinsed with hexane to remove surface lipids, [ 5] 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

RKDF COLLEGE OF PHARMACY Page 26

Page 27: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

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)

RKDF COLLEGE OF PHARMACY Page 27

Page 28: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

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

RKDF COLLEGE OF PHARMACY Page 28

Page 29: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

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

RKDF COLLEGE OF PHARMACY Page 29

Page 30: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

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

RKDF COLLEGE OF PHARMACY Page 30

Page 31: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

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

RKDF COLLEGE OF PHARMACY Page 31

Page 32: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

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

Q = k H t 1/2 ....................................(7)

First-order release equation

Log Q t = LogQ 0 + Kt/2.303 ........(8)

Korsmeyer-Peppas equation

F = (M t /M) = K m t n .......................(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

RKDF COLLEGE OF PHARMACY Page 32

Page 33: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

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

RKDF COLLEGE OF PHARMACY Page 33

Page 34: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

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

RKDF COLLEGE OF PHARMACY Page 34

Page 35: Trans Dermal Drug Delivery

TRANSDERMAL DRUG DELIVERY SYSTEM

RKDF COLLEGE OF PHARMACY Page 35