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 incurring

(ie.peptides;proteins)

significant

immunogenecity

to

their

site

or

biological

of

action

inactivation.

,

without

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

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TRANSDERMAL DRUG DELIVERY SYSTEM

drugs

across

this

layer.

The

method

to

circumvent

the drugs be both water-soluble and lipid soluble. about fifty percent of the drug being each.

this

is

to

engineer

The best mixture is

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

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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.

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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

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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

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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 )

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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.

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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.

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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

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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, 2purrolidone; laurocapram (Azone), miscellaneous solvents – propylene glycol, glycerol, silicone fluids, isopropyl palmitate. b) Surfactants

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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, 4butane 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

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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

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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

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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.

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TRANSDERMAL DRUG DELIVERY SYSTEM

Fig…Diagrammatic representation of the stratum corneum and the intercellular and transcellular routes of penetration

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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

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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.betamethasone17-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

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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 fiveto 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

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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

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TRANSDERMAL DRUG DELIVERY SYSTEM

complexation with HP- -CD had no effect onthe flux of cortisone through hairless mouse skin by either ofthe proposed mechanisms .This remains a controversialarea. 4. Liposomes and Vesicles. There are many examples of cosmetic products in whichthe active ingredients are encapsulated in vesicles. Theseinclude humectants such as glycerol and urea, sunscreeningand tanning agents, enzymes, etc. Although there are fewcommercial topical products containing encapsulated drugs,there is a considerable body of research in the topic. Avariety of encapsulating systems have been evaluatedincluding liposomes, deformable liposomes or transfersomes,ethosomes and niosomes.Liposomes are colloidal particles formed as concentricbiomolecular layers that are capable of encapsulating drugs.Their potential for delivering drugs to the skin was firstreported by Mezei and Gulasekharam in 1980 who showedthat the skin delivery of triamcinolone acetonide was four tofive times greater from a liposomal lotion than an ointmentcontaining the same drug concentration..Phosphatidylcholine from soybean or egg yolk is the mostcommon composition although many other potentialingredients have been evaluated .Cholesterol added tothe composition tends to stabilize the structure therebygenerating more rigid liposomes. Recent studies have tendedto be focused on delivery of macromolecules such asinterferon , gene delivery and cutaneous vaccination, in some cases combining the liposomal

delivery

systemwith

other

physical

enhancement

techniques

such

aselectroporation . Their delivery mechanism is reported tobe associated with accumulation of the liposomes andassociated drug in the stratum corneum and upper skilayers, with minimal drug penetrating to the deeper tissues and systemic circulation (eg.. The mechanism ofenhanced drug uptake into the stratum corneum is unclear. Itis possible that the liposomes either penetrate the stratumcorneum to some extent then interact with the skin lipids torelease their drug or that only their components enter thestratum corneum. It is interesting that the most effectiveliposomes are reported to be those composed of lipidssimilar to stratum corneum lipids , which are likely tomost readily enter stratum corneum lipid lamellae and fusewith endogenous lipids.Transfersomes are vesicles composed of phospholipids astheir main ingredient with 10-25% surfactant (such assodium cholate) and 3-10% ethanol. The surfactantmolecules act as “edge activators”, conferringultradeformability on the transfersomes, which RKDF COLLEGE OF PHARMACY

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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

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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 ------

=

P s ( C d – Cr )

.. ……………………….. (1)

dt where

Cd

and

Cr

are

the

concentration

of

the

skin

penetrant

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

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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

tissues. given

of As

conditions

skin

tissues

Ks

,Dss

the

and

hs

is

and

permeability

the

overall

hs

thickness

are

coefficient

Ps

of

constant

for

a

skin under

skin

penetrant

can be considered to be constant. From equation (1) it is clear that a constant rate

of

i.e.

the

drug drug

permeation

can

concentration

at

be the

obtained surface

only

when

the

stratum

of

Cd

>>

Cr

corneum

Cd

is consistently and substantially greater than the drug concentration in the body Cr. The equation becomes: dQ -------

=

P s Cd

dt And the rate of skin permeation is constant provided the magnitude of Cd remains fairly constant throughout the course of skin permeation. For keeping Cd

constant

Rr

i.e.

the

either

drug

should

be

released

constant

or

greater

than

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from the

the

rate

device of

skin

at

a

uptake

rate Ra

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TRANSDERMAL DRUG DELIVERY SYSTEM

i.e . Rr >> Ra . Since

Rr

skin

>>

surface

Cd

Ra is

,

the

maintained

the

equilibrium

solubility

of

.i.e.

Cd>>Cs.

Therefore

a

at the

drug a

concentration

level

drug

equal

in

maximum

the

rate

to

on

or

greater

stratum of

the

corneum

skin

than Cs

permeation

is obtained and is given by the equation: (dQ/dt)m =

PsCs

From

the

above

skin

permeation

and

is

equation

it

depends

upon

equilibrium

can

solubility

in

be

seen

that

the

skin

the

stratum

the

maximum

permeability corneum

rate

coefficient C s.

Thus

of Ps 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

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psychiatric

treatment.

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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. Longacting modified dosage forms of haloperidol are effective in patients and can help to address the problem of poor patient compliance. The use of this drug in the lowest possible effective dosage is recommended for minimizing the risk of major side effects. Based on these hypotheses, a modified transdermal drug delivery system was developed. Simple drug-matrix dispersion type of transdermal drug delivery system for haloperidol was designed for prolonged period of maintenance therapy instead of convention oral dosage forms. Moreover, the physicochemical characteristics of haloperidol also comply with

the

general

requirement

for

designing

a TDDS

to

a

good

extent.

This search and investigation is expected to add extensively to the existing knowledge and information in the field of proper drug regimen and maintenance therapy of schizophrenia

with

controlled-release

TDDS

of

haloperidol.

Material & method Ethyl cellulose was supplied by S. P. Pharmaceuticals, USA. Polyvinyl pyrrolidone (PVP) K-30 was obtained from S. D. Fine Chemicals, Mumbai, India. Dibutyl phthalate was procured from Central Drug House Ltd., New Delhi. Chloroform was obtained commercially from Ranbaxy Fine Chemicals, New Delhi. Hyaluronidase was obtained from Charles Pharma Ltd. Polyethylene glycol 400 and sodium chloride were purchased from S. D. Fine Chemicals, Mumbai. Haloperidol lactate was received as a gift sample from

Torrent

RKDF COLLEGE OF PHARMACY

Pharmaceuticals,

Ahmedabad. Page 25

TRANSDERMAL DRUG DELIVERY SYSTEM

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 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 RKDF COLLEGE OF PHARMACY

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TRANSDERMAL DRUG DELIVERY SYSTEM

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 1octanol 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 1octanol/water system for 30 min and allowed to stand for 1 h. The mixture was then centrifuged at 2000 rpm for 10 min, and concentration of drug in each phase was determined spectrophotometrically by measuring absorbance at 245 nm. The partition coefficient (Kp) was calculated from the equation.

Permeability coefficient (P): Permeability coefficient is the velocity of drug passage through the membrane in µg/cm 2 /h. The permeability coefficient was calculated from the slope of the graph of percentage of drug transported versus time as, P = slope x Vd/S ..........................................(2) where

Vd

S

=

=

volume surface

of area

donor of

solution; tissue.

Flux ( J): Flux is defined as the amount of material flowing through a unit crossRKDF COLLEGE OF PHARMACY

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TRANSDERMAL DRUG DELIVERY SYSTEM

sectional Flux where

barrier (J) CD

in =

unit P

=

time. x

concentration

It

CD

is

calculated

by

.........................................(3) of

donor P

=

solution; permeability.

Enhancement ratio: Enhancement ratio was used to evaluate the effect of permeation enhancer on diffusion and permeation of selected drug molecules. It is calculated by,

SpectrophotometerUV/VISanalysis Haloperidol lactate was determined using Shimadzu UV spectrophotometer at 245 nm. [ 11] A correlation coefficient of 0.9999 was obtained with a slope value of 0.0351. Drug-excipientinteractionstudy FT-IR spectra of haloperidol lactate, ethyl cellulose, PVP, transdermal film loaded with drug, and adjuvants were taken using Perkin-Elmer FT-IR spectrophotometer (model 1600- KBr disk method). Fifty milligrams of sample and 150 mg of KBr was taken in a mortar and triturated Scanningelectronmicroscopy The external morphology of the transdermal patch was analyzed using a scanning electron microscope (JMS 6100 JEOL, Tokyo, Japan). The samples placed on the stubs RKDF COLLEGE OF PHARMACY

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TRANSDERMAL DRUG DELIVERY SYSTEM

were coated finally with gold palladium and examined under the Microscope and shown in Differentialscanningcalorimetry The thermograms of pure and prepared patches was scanned using ifferential scanning calorimetry. The samples were hermetically sealed in flat-bottomed aluminum pans and heated over a temperature range of 40°C to 240°C at a rate of 10°K/min using alumina as a

reference

standard.

Evaluationoftransdermalpatches Thicknessdetermination The aim of the present study was to check the uniformity of thickness of the formulated films. The thickness was measured at five different points of the film. Using BAKER Digital

caliper,

the

average

of

five

readings

was

calculated.

Uniformityofweight Five different patches from individual batches were weighed individually, and the average weight was calculated; the individual weight should not deviate significantly from the average weight. The tests were performed on films which were dried at 60°C for 4

h

prior

to

testing.

Moisturecontent The film was weighed and kept in a desiccator containing calcium chloride at 40°C and dried for at least 24 h. The film was weighed until it showed a constant weight. The moisture content was the difference between the constant weight taken and the initial weight and was reported in terms of percentage (by weight) moisture content Flatnessandelongationbrake RKDF COLLEGE OF PHARMACY

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TRANSDERMAL DRUG DELIVERY SYSTEM

Longitudinal strips were cut out from the prepared medicated film. The flatness was determined at various points by using vernier calipers calculated. The percentage elongation brake was determined by noting the length just before the break point and substituted in the formula no 5.

where L

1

= final length of each strip; and L

2

= initial length of each strip.

Moistureuptake A weighed film kept in a dessicator at 40°C for 24 h was taken out and exposed to relative humidities of 75% (saturated solution of sodium chloride) and 93% (saturated solution of ammonium hydrogen phosphate) respectively, at room temperature. Then the films

were

measured

periodically

to

constant

weights.

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

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TRANSDERMAL DRUG DELIVERY SYSTEM

respective wavelengths, against a blank solution which was prepared by the same protocol

but

not

containing

drug.

Invitrodiffusionstudy Franz diffusion cell was used for the study of in vitro release patterns of the prepared TDDS formulations. The elution mediums of 20% PEG 400 in normal saline, and epidermis of the fresh human cadaver skin excised from the thigh portion were used as the barrier. The films were placed in between the donor and receptor compartments in such a way that the drug-releasing surface faced the receptor compartment. The receptor compartment was filled with the elution medium, and a small bar magnet was used to stir the medium at a speed of 60 rpm with the help of a magnetic stirrer. The temperature of the elution medium was maintained and controlled at 37°C ± 1°C by a thermostatic arrangement. An aliquot of 1 mL withdrawn at predetermined intervals, being replenished by equal volumes of the elution medium, withdrawal of samples was carried out for a period

of

24

h.

The

drug

concentration

in

the

aliquot

was

determined

spectrophotometrically and was calculated with the help of a standard calibration curve. Dataanalysis The pharmaceutical dosage forms that do not disaggregate and release the drug slowly (assuming that area does not change and no equilibrium conditions are obtained) could be represented by a zero-order kinetic equation. Hixson and Crowell (1931) recognized that the particle regular area is proportional to the cubic root of its volume. Colombo et al. suggested that the quantity of drug from the matrix-type delivery system is often analyzed as a function of the square root of time, which is typical for a system where drug release is governed by pure diffusion. However, this relationship in a transdermal system is not justified completely as such systems can be erodible. Therefore, analysis of drug release from transdermal system must be performed with a flexible model that can identify the contribution to overall kinetics. Dissolution data was treated with different releasekineticequations.

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TRANSDERMAL DRUG DELIVERY SYSTEM

Zero-orderreleaseequation Q

=

k

Higuchi's Q

square =

t

0

root

k

of

time

1/2

t

H

First-order Log

...........................................(6)

....................................(7)

release Q

=

t

LogQ

equation +

0

Kt/2.303

Korsmeyer-Peppas F

=

equation

(M

........(8) equation

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

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TRANSDERMAL DRUG DELIVERY SYSTEM

solubility of the drug in the matrix by sustaining it in an amorphous form. Partition coefficient of haloperidol lactate, in octanol/water system was found to be 1.248. Solubility and permeability of haloperidol lactate were evaluated at various values of pH of phosphate buffer. It was seen that solubility decreases with increase in the pH of phosphate buffer, and the permeability coefficient increases with increase in the value of pH. The permeability studies of haloperidol lactate in a modified Franz diffusion cell through the human cadaver skin showed that the permeability coefficient (P) and flux of haloperidol lactate were 15.96 m/h and 95.76 µg/cm 2 /h respectively. The enhancement ratios of drug with different enhancers were evaluated using modified Franz diffusion cell through human cadaver skin. The permeability coefficient, flux, and enhancement ratio of drug with IPM were found to be 15.45 cm/h, 92.7 µg/cm 2 /h, and 0.986 respectively; and with hyaluronidase, these were found to be 34.18 cm/h, 205.08 µg/cm 2 /h, and 2.141 respectively. CONCLUSION Transdermal drug delivery is hardly an old technology, and the technology no longer is just adhesive patches. Due to the recent advances in technology and the incorporation of the drug to the site of action without rupturing the skin membrane transdermal route is becoming the most widely accepted route of drug administration. It promises to eliminate needles for administration of a wide variety of drugs in the future.The search for the ideal skin penetration enhancer has been the focus of considerable research effort over a number of decades. Although many potent enhancers have been in most cases their enhancement effects are associated with toxicity, therefore limiting their clinical application. In recent years the use of a number of biophysical techniques has aided in our understanding of the nature of the stratum corn eum barrier and the way in which chemicals interact with and influence this structure. A better understanding of the interaction of enhancers with the stra tum corneum and the development of structure activity

relationships for enhancers will aid in the design

ofenhancers with optimal characteristics and minimal toxicity. RKDF COLLEGE OF PHARMACY

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TRANSDERMAL DRUG DELIVERY SYSTEM

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

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