transdermal drug delivery system1

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TRANSDERMAL DRUG DELIVERY SYSTEM

• Introduction:- Transdermal patch of scopolamine is the rst transdermal patch which

is approved by FDA in 1981. Transdermal delivery systems of scopolamine is used for the prevention of motion sicknessTransderm!cop" A#$A %orp.& and nitro'(lycerine for the prevention of an(ina pectoris associated with coronary artery disease Transderm)*itro&. Transdermal dru( delivery products (ive therapeutic benet topatients. Appro+imately 1, active in(redients and more than - Transdermal dru( delivery products have been approved for use(lobally and for sale in the /! respectively. 0n the year 22 market of 3 1.4 billion is found by statistics analysis that is e+pected to increaseto 3 1. billion in the year 211 and 3-1. billion in the year 21. Transdermal dru( delivery systems TDD!&" also known as 5patches"6

are dosa(e forms desi(ned to deliver a therapeutically e7ectiveamount of dru( across a patients skin. 0n order to deliver therapeutica(ents throu(h the human skin for systemic e7ects" thecomprehensive morpholo(ical" biophysical and physicochemicalproperties of the skin are to be considered. Transdermal deliveryprovides a leadin( ed(e over inectables and oral routes by increasin(patient compliance and avoidin( rst pass metabolism respectively 1 . Transdermal delivery not only provides controlled" constantadministration of the dru(" but also allows continuous input of dru(swith short biolo(ical half'lives and eliminates pulsed entry intosystemic circulation" which often causes undesirable side e7ects. Thus

various forms of *ovel dru( delivery system such as Transdermal dru(delivery systems" %ontrolled release systems" Transmucosal deliverysystems etc. emer(ed. !everal important advanta(es of transdermaldru( delivery are limitation of hepatic rst pass metabolism"enhancement of therapeutic e:ciency and maintenance of steadyplasma level of the dru(. The rst Transdermal system" Transderm'!%;< was approved by FDA in 1949 for the prevention of nausea andvomitin( associated with travel" particularly by sea. The evidence of percutaneous dru( absorption may be found throu(h measurable bloodlevels of the dru(" detectable e+cretion of the dru( and its metabolitesin the urine and throu(h the clinical response of the patient to the

administered dru( therapy.!ince the be(innin( of life on the earth" humans have applied a lot of substances to their skin as cosmetics and therapeutic a(ents.=owever" it was the twentieth century when the skin became used asroute for lon( term dru( delivery.Today about two third of dru(savailable in market& are taken orally" but these are not as e7ective asre>uired. To improve upon the features the transdermal dru( deliverysystem was emer(ed.Amon(st all techni>ues which were used for

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release dru(s in a controlled way into the human body" transdermaldru( delivery system TDD!& is widely reco(ni?ed as one of the mostreliable" appealin( as well as e7ective techni>ue. Delivery of dru(sthrou(h the skin has been an attractive as well as a challen(in( areafor research. ;ver the last two decades" transdermal dru( delivery had

become an appealin( and patience acceptance technolo(y as it isminimi?e and avoids the limitations allied with conventional as well asparenteral route of dru( administration such as peak and valleyphenomenon i.e. e+hibit @uctuation in plasma dru( concentration level"pain and inconvenience of inections and the limited controlled releaseoptions of both.

A transdermal patch is dened as medicated adhesive patch which isplaced above the skin to deliver a specic dose of medication throu(hthe skin with a predetermined rate of release to reach into thebloodstream. Today the most common transdermal system present inthe market mainly based on semi permeable membranes which were

called as patches. Transdermal dru( delivery system is dened as the topicallyadministered medications in the form of patches which when applied tothe skin deliver the dru(" throu(h the skin at a predetermined andcontrolled rate. Transdermal patches are delivered the dru( throu(h theskin in controlled and predetermined manner in order to increase thetherapeutic e:cacy of dru( and reduced side e7ect of dru(. %ontrolleddru( release can be achieved by transdermal dru( delivery systemsTDD!& which can deliver the dru( via the skin portal to systemiccirculation at a predetermined rate over a prolon(ed period of time.1For e7ective Transdermal dru( delivery system" the dru( are easily able

to peneterate the skin and easily reach the tar(et site. TDD! increasethe patient compliance and reduces the load as compared to oral route.FDA approved the rst Transdermal system Transderm'!%;< in 1949.FDA approved this for the prevention of nausea and vomitin( associatedwith ravel" particularly by sea. Transdermal therapeutic systems arealso dened as a self contained" discrete dosa(e forms which" whenapplied to the intact skin" deliver the dru(" throu(h the skin at controlrate to the systemic circulation. Transdermal formulation maintain dru(concentration within the therapeutic window for prolon( period of timeensurin( that dru( levels neither fall below the minimum e7ectiveconcentration nor e+ceed the ma+imum e7ective concentration.

The common in(redients which are used for the preparation of TDD!are as followsB'

1.Drug:- Dru( is in direct contact with release liner.C+B *icotine"ethotre+ate and Cstro(en.

2.Liners:-


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.Ad!esi"e:- !erves to adhere the patch to the skin for systemicdelivery of dru(. C+B Acrylates" uality of sleep and reduces the ci(arette smokin(conditions.

d0 Reser"oir s+ste%:- 0n this system the dru( reservoir isembedded between an impervious backin( layer and a rate controllin(membrane. The dru( releases only throu(h the ratecontrollin(membrane" which can be micro porous or non porous. 0n the dru(reservoir compartment" the dru( can be in the form of a solution"suspension" (el or dispersed in a solid polymer matri+. =ypoaller(enicadhesive polymer can be applied as outer surface polymericmembrane which is compatible with dru(.

e0 M&tri3 s+ste%:-

i. Drug-in-&d!esi"e s+ste%:- 0n this type the dru( reservoir isformed by dispersin( the dru( in an adhesive polymer and thenspreadin( the medicated adhesive polymer by solvent castin( ormeltin( in the case of hot'melt adhesives& on an impervious backin(layer. ;n top of the reservoir" unmediated adhesive polymer layers areapplied for protection purpose.



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ii. M&tri3-disersion s+ste%: 0n this type the dru( is dispersedhomo(enously in a hydrophilic or lipophilic polymer matri+. This dru(containin( polymer disk is +ed on to an occlusive base plate in acompartment fabricated from a dru( impermeable backin( layer.0nstead of applyin( the adhesive on the face of the dru( reservoir" it is

spread alon( with the circumference to form a strip of adhesive rim.

f) Microreser"oir s+ste%: 0n this type the dru( delivery system isa combination of reservoir and matri+'dispersion system. The dru(reservoir is formed by rst suspendin( the dru( in an a>ueoussolution of water soluble polymer and then dispersin( the solutionhomo(eneously in a lipophilic polymer to form thousands of unreachable" microscopic spheres of drug reservoirs. This thermodynamicallyunstable dispersion is stabilized quickly by immediately cross-linking the polymer in

situ by using cross linking agents.

• VARI,US MET/,DS ,R $RE$ARATI,N TDDS:-

&. As+%%etric T$4 %e%r&ne %et!od:- A prototype patchcan be fabricated for this a heat sealable polyester lm type 1229"-m& with a concave of 1cm diameter will be used as the backin(membrane. Dru( sample is dispensed into the concave membrane"covered by a T


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homo(enous dispersion and poured in to a leveled mercurysurface" covered with inverted funnel to control solventevaporation.

d.(+ using 6I$M %e%r&nes7 %et!od:- 0n this method dru(is dispersed in a mi+ture of water and propylene (lycol containin(carbomer 9I2 polymer and stirred for 1 hrs in ma(netic stirrer. Thedispersion is to be neutrali?ed and made viscous by the addition of triethanolamine. Nu7er p= 4.I can be used in order to obtain solution(el" if the dru( solubility in a>ueous solution is very poor. The formed(el will be incorporated in the 0ue. From the earlier reference dru( and lecithin in the ratio of 2.1B.2 can be used as an optimi?ed one. The proliposomes areprepared by takin( m( of mannitol powder in a 122 ml round bottom@ask which is kept at ,2'42Mc temperature and the @ask is rotated at82'92 rpm and dried the mannitol at vacuum for -2 minutes. After

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dryin(" the temperature of the water bath is adusted to 2'-2M%. Dru(and lecithin are dissolved in a suitable or(anic solvent mi+ture" a 2.mlali>uot of the or(anic solution is introduced into the round bottomed@ask at -4M%" after complete dryin( second ali>uots 2.ml& of thesolution is to be added. After the last loadin(" the @ask containin(

proliposomes are connected in a lyophili?er and subse>uently dru(loaded mannitol powders proliposomes& are placed in a desiccatorover ni(ht and then sieved throu(h 122 mesh. The collected powder istransferred into a (lass bottle and stored at the free?e temperatureuntil characteri?ation.

!.(+ using 5ree 5i*% %et!od:- Free lm of cellulose acetate isprepared by castin( on mercury surface. A polymer solution O wKw isto be prepared by usin( chloroform.


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Ad"&nt&ges o5 Tr&nsder%&* drug de*i"er+ s+ste%:-

Avoidance of rst pass metabolism of dru(s. Transdermal medication delivers a steady infusion of a dru( over a

prolon(ed period of time. Adverse e7ects or therapeutic failuresfre>uently associated with intermittent dosin( can also be avoided.

The simplied medication re(imen leads to improved patientcompliance and reduced the side e7ects" inter and intra'patientvariability.*o interference with (astric and intestinal @uids.

aintains stable or constant and controlled blood levels for lon(erperiod of time.

%omparable characteristics with interavenous infusion.0t increases the therapeutic value of many dru(s via avoidin( specicproblems associated with the dru( like Q0 irritation" lower absorption"decomposition due to Rhepatic rst pass e7ect.

This route is suitable for the administration of dru(s havin( veryshort half life" narrow therapeutic window and poor oral availability.0mproved patient compliance and comfort via non'invasive" painlessand simple application..

Fle+ibility of terminatin( the dru( administration by simply removin(

the patch from the skin. !elf administration is possible in these system.

Dis&d"&nt&ges o5 Tr&nsder%&* drug de*i"er+ s+ste%:-

The possibility of local irritation may develop at the site of application. any problems like Crythema" itchin(" and local edemacan be caused by the dru(" the adhesive" or other e+cipients in thepatch formulation.

Dru(s has lar(e molecular si?e makes absorption di:culty. !o dru(molecule should ideally be below 822'1222 daltons.any dru(s with a hydrophilic structure havin( a low peneterationthrou(h the skin and slowly to be of therapeutic benet. Dru(s with alipophillic character" however" are better suited for transdermaldelivery.

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The barrier function of the skin chan(es from one site to another onthe same person" from person to person and with a(e.

AT,RS AETING TRANSDERMAL DRUG DELIVERY

SYSTEM:-

L&+ers o5 s)in:- Three maor layers of the skin areCpidermis. Dermis. =ypodermis.

S8IN :-!tructure of !kin The human skin is a mutilayered or(ancomposed of many histolo(ical layers. !kin is most accessible or(an inbody. 0ts maor functions are protection of maor or vital internalor(ans from the e+ternal in@uences" temperature re(ulations" controlof water output and sensation. The skin of an avera(e adult bodycovers appro+imately surface area of two s>uare meters and receivesabout one'third of the blood circulatin( throu(h the body. !kin is thecomple+ or(an and allows the passa(e of various chemicals into andacross the skin. !kin serves as the point of administration forsystemically active dru(s" the dru( applied topically will be absorbed"

rst into the systemic circulation and then transported to tar(et tissue

Eider%is:- The epidermis is a stratied" s>uamous" keratini?in(epithelium. The keratinocytes comprise the maor cellular componentS 92O& and the responsible for the evolution of barrier function.eratinocytes chan(e their shape" si?e and physical properties whenmi(ratin( to the skin surface. ;ther cells present which are present in

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Biological factors Physiological factors

!kin condition Temperature and p=

!kin a(e Di7usion coe:cient

Nlood @ow Dru( concentration

Ee(ional skin site !kin hydration

!pecies Di7erences


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this layer include elanocytes" #an(erhans cells and arkel cells" noneof which appears to contribute to the physical aspects of the barrier.icroscopically" the epidermis further divided into ve anatomicallayers with stratum corneum formin( the outer most layer of theepidermis" e+posin( to the e+ternal environment. !tratum corneum is

the outermost layer of epidermis appro+imately 122'12 micrometersthick" has no blood @ow. This is the layer most important totransdermal delivery as its composition allows it to keep water withinthe body and forei(n substances out. Neneath the epidermis" thedermis contains the system of capillaries that transport bloodthrou(hout the body. 0f the dru( is able to penetrate the stratumcorneum" then it can enter the blood stream. A process known aspassive di7usion" which occurs too slowly" is the only means to transfernormal dru( across the layer.

Der%is:- The dermis is the inner and lar(er 92O& skin layer"

comprises primarily of connective tissue and provides supports to theepidermis layer of the skin. The boundary between dermis andepidermis layer is called Dermal' Cpidermal unction which provides aphysical barrier for the lar(e molecules of dru( and cells. The dermisincorporates blood and lymphatic vesicles and nerve endin(s. Thee+tensive microvasculature network which is found in the dermisrepresents the site of resorption for dru(s absorbed across theepidermis. The dermis can be divided into two anatomical re(ionpapillary dermis and reticular dermis.


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• Ai% &nd $ro9ect

Need 5or t!e stud+:- Transdermal Dru( Delivery !ystem is thesystem in which the delivery of the active in(redients of the dru(occurs throu(h the skin. Transdermal dru( delivery system can improvethe therapeutic e:cacy and safety of the dru(s because dru( deliveredthrou(h the skin at a predetermined and controlled rate. !kin is theimportant site of dru( application for both the local and systemice7ects. !kin of an avera(e adult body covers a surface of appro+imately m and receives about one'third of the bloodcirculatin( throu(h the body. !kin is an e7ective medium from whichabsorption of the dru( takes place and enters the circulatory system.arious types of Transdermal patches are used that delivered thespecic dose of medication directly into the blood stream. This reviewarticle covers a brief outline of the trasdermal dru( delivery system"advanta(es over conventional dru( delivery system" #ayers of the skin"various components of transdermal patch" penetration enhancers" andevaluation of transdermal system and applications of Transdermalpatch.Transdermal patches are pharmaceutical preparation of varyin(si?es" containin(" one or more active in(redient" intended to be appliedto the unbroken skin in order to deliver the active in(redient to thesystemic circulation after passin( throu(h the skin barriers" and it avoidrst pass e7ect. Transdermal patches delivers the dru(s for systemice7ects at a predetermined and controlled rate. Throu(h a di7usionprocess" the dru( enters the bloodstream directly thou(h the skin. !incethere is hi(h concentration on the patch and low concentration in theblood" the dru( will keep di7usin( into the blood" the dru( will keepdi7usin( into the blood for a lon( period of time" maintainin( theconstant concentration of dru( in the blood @ow. %haracteri?ation of transdermal patch is use to check its >uality" si?e" time of onset Uduration" adhesive property" thickness" wei(ht of patch" moisture of content" uniformity U cutaneous to+icolo(ical studies. The market for

transdermal products has been in a si(nicant upward trend that islikely to continue for the foreseeable future. An increasin( number of TDD products continue to deliver real therapeutic benet to patientsaround the world. ore than - TDD products have now been approvedfor sale in the /!" and appro+imately 1, active in(redients areapproved for use in TDD products (lobally.

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• Liter&ture Re"ie

M&r) R. $r&usnit;".et al."(222&B' The past twenty ve yearshave seen an e+plosion in the creation and discovery of new medicinala(ents. Eelated innovations in dru( delivery systems have not onlyenabled the successful implementation of many of these novelpharmaceuticals" but have also permitted the development of newmedical treatments with e+istin( dru(s. The creation of transdermal

delivery systems has been one of the most important of theseinnovations" o7erin( a number of advanta(es over the oral route. 0nthis article" we discuss the already si(nicant impact this eld hasmade on the administration of various pharmaceuticals"e+plorelimitations of the current technolo(y and discuss methods undere+ploration for overcomin( these limitations and the challen(es ahead.

$5ister


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microneedles, thermal ablation" microdermabrasion" electroporationand cavitational ultrasound. icroneedles and thermal ablation arecurrently pro(ressin( throu(h clinical trials for delivery of macromolecules and vaccines" such as insulin" parathyroid hormoneand in@uen?a vaccine

Roert L&nger".et al."22-&B' Transdermal delivery representsan attractive alternative to oral delivery of dru(s and is poised toprovide an alternative to hypodermic inection too1WI. For thousands of years" people have placed substances on the skin for therapeutice7ects and" in the modern era" a variety of topical formulations havebeen developed to treat local indications. The rst transdermal systemfor systemic deliveryXa three'day patch that delivers scopolamine totreat motion sicknessXwas approved for use in the /nited !tates in1949.

/e&t!er A.E. (enson:- 1984There is considerable interest in theskin as a site of dru( application both for local and systemic e7ect.=owever" the skin" in particular the stratum corneum" poses aformidable barrier to dru( penetration thereby limitin( topical andtransdermal bioavailability. !kin penetration enhancement techni>ueshave been developed to improve bioavailability and increase the ran(eof dru(s for which topical and transdermal delivery is a viable option. This review describes enhancement techni>ues based on dru(Kvehicleoptimisation such as dru( selection" prodru(s and ion'pairs"supersaturated dru( solutions" eutectic systems" comple+ation"liposomes" vesicles and particles. Cnhancement via modication of thestratum corneum by hydration" chemical enhancers actin( on thestructure of the stratum corneum lipids and keratin" partitionin( andsolubility e7ects are also discussed. The mechanism of action of penetration enhancers and retarders and their potential for clinicalapplication is described

$.M.$&ti*,.et al".21&B' Dru( delivery system relates to theproduction of a dru(" its delivery medium" and the way of administration. Dru( delivery systems are even used for administerin(nitro(lycerin. Transdermal dru( delivery system is the system in which

the delivery of the active in(redients of the dru( occurs by the meansof skin.

Ni)!i* S!&r%&,.et al."(211&B' There has been little chan(e in thecomposition of the patch systems. odications have been mostlylimited to renements of the materials used. The present review article


http://www.ncbi.nlm.nih.gov/pubmed/?term=Langer%20R%5Bauth%5Dhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2700785/#R1http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2700785/#R4http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2700785/#R4http://www.ncbi.nlm.nih.gov/pubmed/?term=Langer%20R%5Bauth%5Dhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2700785/#R1http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2700785/#R4


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e+plores the overall study on transdermal dru( delivery system TDD!&which leads to novel dru( delivery system *DD!&.

8u%&r> =. As!o),.et al."22I&B' Today about 4IO of dru(s aretaken orally and are found not to be as e7ective as desired. To improve

such characters transdermal dru( delivery system was emer(ed. Dru(delivery throu(h the skin to achieve a systemic e7ect of a dru( iscommonly known as transdermal dru( delivery and di7ers fromtraditional topical dru( delivery. Transdermal dru( delivery systemsTDD!& are dosa(e forms involves dru( transport to viable epidermaland or dermal tissues of the skin for local therapeutic e7ect while avery maor fraction of dru( is transported into the systemic bloodcirculation.

G!os! $.T!e>.et al." (21, &B'

*avi(atin( sticky areas in transdermal product developmentbenet of transdermal delivery over the oral route to combatsuch issues of low bioavailability and limited controlled releaseopportunities are well known and have been previously discussedby many in the eld


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$te* = /ou),.et al.,(1999):- The mechanism of action of penetration enhancers and retarders and their potential for clinicalapplication is described Transdermal dru( delivery system is thesystem in which the delivery of the active in(redients of the dru(occurs by the means of skin.

8.A*"in,.et al.,(200):- This review describes enhancementtechni>ues based on dru(Kvehicle optimisation such as dru( selection"prodru(s and ion'pairs" supersaturated dru( solutions" eutecticsystems" comple+ation" liposomes" vesicles and particles. idealproperties of enhancers and describe various enhancersV actions on theskin.


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S8IN AS A SITE ,R DRUG INUSI,N:- The skin is the lar(est or(an of the body. The skin an avera(e adultbody is about 2 s>uare feet and it received about one third of total

available blood. The skin is multilayered or(an composed of threehistolo(ical tissueB'

the outermost layer of skin"epidermis is which provides a waterproof barrier and creates our skin tone.

dermis" beneath epidermis" contains tou(h connective tissue" hairfollicles" and sweat (lands and deeper subcutaneous tissuehypodermis& is made of fat and connective tissue.1. TranscellularK0ntracellular permeation throu(h the stratum corneum. 0ntercellular permeation throu(h the stratum corneum-. Transappenda(eal permeation via the hair follicles" sweat andsebaceous (lan."

Mec!&nis% o5 tr&nsder%&* er%e&tion:- Transdermal permeation of a dru( moiety involves the followin( stepsBi. !orption by stratum corneumii. uationB'Ps( Cd –Cr)Yhere" %dZ concentration of penetrate in the donor phase on thesurface of skin %r Z concentration of penetrate in the receptor phasebody.



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Fig.. !i"erent ro#te of s$in penetration

A constant rate of dru( permeation achieved" if %d S%r thenthe e>uation reduced asB'd%&d'Ps.Cd

the rate of skin permeation d[Kdt& becomes a constant" if the %valueremains fairly constantthrou(hout the course of skin permeation Tomaintain the %dat a constant value" it is critical tomake the dru( tobe released at a rate Er& which is always (reater than the rate of skinuptake. Ny doin( so" the dru( concentration on the skin surface %d& ismaintained at a level which is always (reater than the e>uilibrium orsaturation& solubilityof the dru( in the stratum corneum and ma+imumrate of skin permeation.Apparently" the ma(nitude of d[Kdo&mis determined by the skinpermeability coe:cient uilibrium solubility inthe stratum conium%es&.

(&sic co%onents o5 tr&nsder%&* s+ste%:-$o*+%er %&tri3 or %&trices:-


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onsider&tions 5or o*+%er se*ection in tr&nsder%&*de*i"er+ s+ste%:- !hould be stable and non'reactive with the dru( moiety.

Casily available" fabricated and manufactured in to desiredformulations.

The properties of polymer e.(. molecular wei(ht (lass transtitiontemp.meltin( point and chemical functionality etc. should be such thatdru( can easily di7used throu(h it and with other components ofsystem.

echanical properties should not chan(e if lar(e amount of dru(incorporate.

!hould provide consistent release of dru( throu(hout the life ofsystem.

T!e o*+%ers used in tr&nsder%&* s+ste% &re:-

N&tur&* $o*+%ers:- e.(. ?ein" (elatin cellulose derivatives" (ums"natural rubber"shellac" wa+es and chitosan etc.

S+nt!etic E*&sto%ers:- e.(." hydrin rubber" polyisobutylenepolybutadiene" silicon rubber" nitrile" "neoprene"butylrubber"acrylonitrile etc.

S+nt!etic $o*+%ersB e.(. polyvinylchloride"polyethylene"polyvinylalcohol" polypropylene" polyamide"polyacrylate" polyurea" "polymethylmethacrylate etc.

$o*+%ers used in tr&nsder%&* s+ste% in "ers&ti*e

%&nner suc! &s:-

R&te contro**ing %e%r&ne:- 0t control the release of dru(by disperse throu(h an inert polymer matri+.The polymer powderblended with dru( moiety by physical manner and then moulded into desired shape with re>uired thickness and surface area.

Ad!esi"e:- make an intimate contact between the skinandtransdermal system. 0t carries the dru( which is dissolved or

dispersed in solution or suspension form.The >uality of dru( di7usedin to skin dependin( on the holdin( power.

$ressure sensiti"e &d!esi"e:- =itherto the rapidity oftransdermal system can be done by pressure sensitive adhesive. The three most commonly usedadhesives arepolyisobutylene"polyacrylate and silicones in TDD Devices.

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Re*e&se *iners:- The patch is covered by protective liner durin(stora(e until it is used .The release liner removed and discarded ustbefore the application of patch over the skin since release liner is inintimate contact with the transdermal system hence it should bephysically as well as chemically inert. The release liner is composed

of a base layer which may be non'occlusive e.(. paper fabric& orocclusive e.(. polyethylene" polyvinylchloride& and a releasecoatin( layer made up of silicon or Te@on. ;ther materials used asrelease liner in transdermal patches include polyester foil andmetali?ed laminate.

(&c)ing *&%in&te:-Yhile desi(n the bakin( layer followin(points must be in considerationB

ust be @e+ible. =avin( low water vapour transmission rate so as to promote skin

hydration and thus (reater skin permeability of dru( !hould be compatible with transdermal system as remain in use

while applyin(. !hould be chemical resistance. =avin( (ood tensile stren(th. *on irritant

C+amples of backin(s laminate are polyethylene lm" polyester lm"and polyolen lm" and aluminumvapor coated layer.

Drug: Transdermal delivery of dru(s has taken a sur(e ofpopularitynowadays. arious physicochemical"pharmacokinetic and

pharmacolo(ical properties of the dru(should be considered fortransdermal system development.Necause of the limited permeabilityof the skin" dru(s have to be transdermally delivered by passivedi7usion throu(h the skin" and are limited by several substantialconstraints. The dru( moiety for transdermal system should be potent dose inm(&" havin( molecular wei(ht \ 1222 ade>uate solubility in thevehicle" lo(< value of ] " meltin( point of 22 M% and appropriatelipophilicity" under(oe+tensive presystemic metabolism" non'ionic and non'irritantareconsidered as suitable candidates for delivery via this route.

$enetr&tion en!&ncers:- %ompounds which promote thepenetration of topically applied dru(s are commonly referred asabsorption promoters" accelerants" or penetration enhancers.


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Desired roerties 5or enetr&tion en!&ncers:-

i. 0t should be non'irritant" non'sensiti?in(" nonphototo+ic" and noncomedo(enic.ii. ;nset of action should be rapid and duration of activity should bepredectible and reproducible.iii. =ave no pharmacolo(ical activity in the body i.e. should not bind tothe receptor site.iv. /pon removal of the enhancer" the upper layer should immediatelyand fully recover its normal barrier property.v. The barrier function of the skin should reduce in one direction onlyCndo(enous material should not be lost to the environment bydi7usion out of the skin.vi. The accelerants should be chemically and physically compatiblewith all dru(s and aduvants to be formulated in topical preparations

and devicesvii. 0t should be ine+pensive" tasteless and colourless"viii. 0t should readily formulated in to dermatolo(ical preparations.i*. 0t should have a desired solubility parameter that appro+imates thatof skin.*. 0t should adhere and spread well on the skin with a suitable skinfeel.!ome of the e+amples of the widely used classicalenhancersinvolve various classes that include water"hydrocarbonsalcohols" acids amines" amides" esters" surfactantterpenes"terpenoidsand essential oil" sulfo+ides" lipidsandmiscellaneous such as cyclode+trin derivatives" chitosan etc.

,t!er e3ciients:-

$*&stici;ers:-


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Aro&c!es in t!e de"e*o%ent o5 tr&nsder%&*t!er&eutic s+ste%:-

!everal technolo(ies have been successfully developed to provide arate control over the release and the transdermal permeation of dru(s.

These technolo(ies are as followsB'1.Ad!esi"e disersion t+e s+ste%:- The system consists of dru('impermeable backin( membrane" the dru( reservoir which isprepared by directly dispersin( the dru( in an adhesive polymer andthen spreadin( the medicated adhesive by solvent castin( or hotmeltin( onto a @at sheet of dru('impermeable backin( to form a thindru( reservoir layer. ;n top of this" a layer of rate'controllin( adhesivepolymer non'medicated& of constant thickness is spread to produce anadhesive di7usion'controlled dru( delivery system with detachablerelease liner which in an ideal situation is removed and the patch is

applied to the skin for a re>uired period of time. 0llustration of this typeof system is e+emplied by development and marketin( of transdermaltherapeutic system of an(ina pectoris and alsartan as an(iotensin 00type 1 selective blocker for one day medication.

2.Me%r&ne er%e&tion contro**ed s+ste%:-0n thissystem the dru( reservoir is totally embedded in a compartmentmolded between a dru('impermeable backin( laminate and a ratecontrollin( polymeric simply by di7usion process throu(h themembrane The pores. 0n the reservoir compartments the dru( solidsare dispersed homo(enously in a solid polymeric matri+ e.(.

polyisobutylene& suspended in the unleachable viscous li>uid mediume.(. silicon @uid& to form a (el'like suspension" or dissolved in areleasable solvent e.(. alkyl alcohol& to form a (el like in solution. Therate controllin( membrane" can be either a microporous or non'porouspolymeric membrane e.(. ethyleneWvinyl acetate copolymer" havin(specic dru( permeability. ;n the top surface of the polymericmembrane a thin layer of dru( compatible adhesive polymer" e.(."silicone adhesives" can be applied" to provide intimate contact of thetransdermal system with the skin surface. The release rate from thistransdermal system can be tailored by varyin( the polymer

composition" thickness of the rate controllin( membrane " permeabilitycoefcient and adhesive. C+amples of this system are Transderm!cop!copolamine' - days protection& of motion sickness and Transderm*itro *itro(lycerine'for once a day &medication of an(inapectoris.



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.M&tri3 di55usion contro**ed s+ste%:- 0n this approach" thedru( reservoirs are prepared by homo(eneously dispersin( dru(particles in a hydrophilic or lipophilic polymer matri+ or combination of both.. The resultant medicated polymer is then molded into amedicated disc with a dened surface area and controlled thickness.

The dispersion of dru( particles in polymer matri+ can be accomplishedby either homo(enously mi+in( the nely (round dru( particles with ali>uid polymer or a hi(hly viscous base polymer followed by crosslinkin( of the polymer chains or homo(enously blendin( dru( solidswith a rubbery polymer at an elevated temperature andKor undervacuum. The polymer disc which contains dru( reservoir is +ed ontoan occlusive base plate in a compartment fabricated from a dru('impermeable backin(. The adhesive polymer is then spread to form astrip of rim alon( the medicated disc. This matri+ type of transdermalsystem is best e+ampled by the nitro(lycerinreleasin( transdermal

therapeutic system. The advanta(e of matri+ dispersion typetransdermal systemis the absence of the dose dumpin( since thepolymer cannot rupture.

#.Microreser"oir t+e contro**ed s+ste%:- This system isbasically hybrid of reservoir and matri+dispersion type of dru( deliverysystem.0n this approach" dru( reservoir is formed by suspendin( thedru( in an a>ueous solution of li>uid polymer and then dispersin( thedru( suspension homo(eneously in a lipophilic polymer e.(.siliconeelastomers by hi(h ener(y dispersion techni>ue by shear mechanical

force to form thousands of unreachable" and microscopic spheres ofdru( reservoirs. This technolo(y has been utili?ed in the developmentof *itro disc. Eelease of a dru( from a micro reservoir'type system canfollow either a partition'control or a matri+ di7usion'control dependin(upon the relative ma(nitude of solubility of the dru( in the li>uidcompartment and in the polymer matri+. cross linkin( of the polymerchains or homo(enously blendin( dru( solids with a rubbery polymerat an elevated temperature andKor under vacuum. The polymer discwhich contains dru( reservoir is +ed onto an occlusive base plate in acompartment fabricated from a dru('impermeable backin(. Theadhesive polymer is then spread to form a strip of rim alon( the

medicated disc. This matri+ type of transdermal system is beste+ampled by the nitro(lycerinreleasin( transdermal therapeuticsystem. The advanta(e of matri+ dispersion type transdermal systemisthe absence of the dose dumpin( since the polymer cannot rupture.Dru('impermeable backin( laminate and a rate controllin( polymericsimply by di7usion process throu(h the membrane The pores. 0n thereservoir compartments the dru( solids are dispersed homo(enously in



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a solid polymeric matri+ e.(. polyisobutylene& suspended in theunleachable viscous li>uid medium e.(. silicon @uid& to form a (el'likesuspension" or dissolved in a releasable solvent e.(. alkyl alcohol& toform a (el like in solution. The rate controllin( membrane" can beeither a microporous or non'porous polymeric membrane e.(.

ethyleneWvinyl acetate copolymer" havin( specic dru(.

• $rer&tion And E"&*u&tion

Transdermal patches of clopido(rel bisulfate were prepared by solventcastin( techni>ue Cthanolic solution of polymer and dru( alon( withpolyethylene (lycol plastici?er& was prepared. The homo(enousmi+ture was poured into plastic mould. The solvent was allowed to

evaporate at controlled rate by placin( an inverted funnel over theplastic mould. The control of evaporation is necessary for uniformdryin( of lms. The dryin( was carried out at room temperature forduration of I hours. After I hours the dry lms was removed fromplastic mould and stored in desiccators until used.

'a+le - Formulation %omposition of Nlank Transdermal


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'a+le 1- %omposition of various Dru( #oaded Transdermal


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area of II.1&cm was used.


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with the same solvent. The solution obtained kept untouched for 1hour to settle down then supernatant diluted as re>uired. The dilutesolution was ltered by membrane havin( pore si?e 2.`m andanaly?ed with suitable analytical =ue and thecalculation was done for dru( content.

?.$ercent&ge Moisture ontent:- The prepared lms werewei(hed individually and kept in a desiccator containin( fused calciumchloride at room temperature for I&h. After I&hours.

In Vi"o Drug Re*e&se Studies :-0n itro dru( release studies were performed by usin( a Fran?di7usion cell with a receptor compartment capacity of ,2&m#. The cellulose acetate membrane was used for the determinationof dru( from the prepared transdermal matri+'type patches. Thecellulose acetate membrane havin( a pore si?e 2.I& μ wasmounted between the donor and receptor compartment of thedi7usion cell. The prepared transdermal lm was placed on thecellulose acetate membrane and covered with aluminum foil. Thereceptor compartment of the di7usion cell was lled withphosphate bu7er p= 4.I. The whole assembly was +ed on a hotplate ma(netic stirrer" and the solution in the receptorcompartment was constantly and continuously stirred usin(ma(netic beads" and the temperature was maintained at -&L&2.M%" because the normal skin temperature of human is -M%. The samples were withdrawn at di7erent time intervals andanaly?ed for dru( content spectrophotometrically. The receptorphase was replenished with an e>ual volume of phosphate bu7erat each sample withdrawal.

In Vitro $er%e&tion Studies:-An in vitro permeation study was carried out by usin( Fran?di7usion cell. Full thickness abdominal skin of male Yistar ratwei(hin( 22 to 2&( was used. =air from the abdominalre(ion was removed carefully by usin( an electric clipper thedermal side of the skin was thorou(hly cleaned with distilledwater to remove any adherin( tissues or blood vessels"e>uilibrate for an hour in phosphate bu7er p= 4.I before startin(

the e+periment" and was placed on a ma(netic stirrer with asmall ma(netic needle for uniform distribution of the di7usant. The temperature of the cell was maintained at -&L&2.M%usin( a thermostatically controlled heater. The isolated rat skinpiece was mounted between the compartments of the di7usioncell" with the epidermis facin( upward into the donorcompartment. !ample volume of &m# was removed from thereceptor compartment at re(ular intervals" and an e>ual volume



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of fresh medium was replaced. !amples were ltered throu(hwatman lter and were analy?ed usin( !himad?u / 1822double'beam spectrophotometer !himad?u" yoto" apan&. Flu+was determined directly as the slope of the curve between thesteady'state values of the amount of dru( permeated m(_cm&

versus time in hours and permeability coe:cient was deducedby dividin( load m(_cm&.

• Resu*t &nd Discussion

$re*i%in&r+ Stud+:-

All the batches of transdermal patch showed thickness variation ran(efrom2.1 to 2.2 mm as shown in . =i(h thickness of batch


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were also obtained to nd out if there was any chemical interactionbetween dru( and the polymer. Ctorico+ib showed characteristic peak

at 11I- cm'1 correspondin( to sulphone (roups '!Z;& and did notalter even after loadin( into the membrane" this conrms stability nointeraction& of the dru( fg. 2&. FT0E of =


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concentration of plastici?er 0t was noticed that formulation D8 showedhi(hest tensile stren(th of I.48 k(Kcm %hitosanK=uation and the re(ression value was found tobe in the ran(e of E Z 2.88 2.9984& which conrm rst orderrelease pattern. Further to nd out whether di7usion is involved in thedru( release" the data was subected to =i(uchis e>uation.

The lines obtained were comparatively linear E Z 2.8I8,2.94,&su((estin( the di7usion may be mechanism of dru( release. To conrmfurther the release mechanism of dru(" the data was subected toorsmeyers'uation. The release e+ponent Rn value wasdetermined" based on Rn value it can be e+plained that incorporated

dru( release by the anomalous *on'Fickian& type of di7usion"involvin( swellin( of the polymer matri+" as is evident by the slopevalues of more than 2. but less than 1 for the plot of lo( cumulativeamount release s lo( time orsmeyers'


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The skin permeation studies were carried out usin( rat skin. Theapparatus for the study was arran(ed in the same manner as fordialysis membrane permeation study. The results are shown in the . Asdone in previous e+periment" the dru( permeation data was plotted accordin( to rst order" =i(uchis and orsemeyer'uation to

know the release mechanisms. The formulations showed the fairlinearity with respect to rst order .E Z 2.98I-2.91-8& and =i(uchis e>uations E Z 2.9,9,2.9-,&hence to conrm precisely the domination mechanism the data wasplotted accordin( to orsemeyers e>uation. The lines obtained werelinear E Z 2.9I,12.9,&" slope values vary between 2.,1,2 and2.,49&.were eliminated for further study. Natch


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0n itro cumulative dru( release studies of formulation cross linkedsodium citrate



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• ,NLUSI,N

This article provide an valuable information re(ardin( the transdermaldru( delivery systems and its evaluation process details as a ready

reference for the research scientist who are involved in TDD!. The

fore(oin( shows that TDD! have (reat potentials" bein( able to use for

both hydrophobic and hydrophilic active substance into promisin(

deliverable dru(s. To optimi?e this dru(

delivery system" (reater understandin( of the di7erent mechanisms of

biolo(ical interactions" and polymer are re>uired. TDD! a realistic

practical application as the system. !ince 1981" transdermal dru(

delivery systems

have been used as safe and e7ective dru( delivery devices. Their potential role in controlled release is bein( (lobally e+ploitedby the scientists with hi(h rate of attainment. 0f a dru( has ri(ht mi+ ofphysical chemistry and pharmacolo(y" transdermal delivery is aremarkable e7ective route of administration. Due to lar(e advanta(esof the TDD!" many new researches are (oin( on in the present



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day to incorporate newer dru(s via the system. A transdermal patchhas several basic components like dru( reservoirs" liners"adherents" permeation enhancers" backin( laminates" plastici?ers andsolvents" which play a vital role in the release of dru( via skin.After preparation of transdermal patches" they are evaluated for

physicochemical studies" in vitro permeation studies" skin irritationstudies"animal studies" human studies and stability studies. Nut all preparedand evaluated transdermal patches must receive approvalfrom FDA before sale. Future developments of TDD!s will likely focuson the increased control of therapeutic re(imens and thecontinuin( e+pansion of dru(s available foruse. Transdermal dosa(e forms may provide clinicians an opportunityto o7er more therapeutic options to their patients to optimi?e theircare.

• Re5erences

ain" *. %ontrolled and *ovel Dru( Delivery" %N!


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!harma *"


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umar A"


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iayan" ." !umanth" .=." !uman" #." vinay" T."!rinivasrao" D." umar. .." Development and physiochemical" in'vitroevaluation of transdermal


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SRMSCET (PHARMACY) BAREILLY 3!


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SRMSCET (PHARMACY) BAREILLY 3"


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transdermal drug delivery system1

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