Transdermal Drug Delivery Systems : A Review

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Girish Chopda

Girish Chopda

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.(1)

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 (ie site specific ) , spatial and temporal placement within
the body thereby reducing both the size and number of doses. New drug delivery
system are also essential for the delivery of novel , genetically engineered
pharmaceuticals (ie peptides , proteins ) to their site of action , without
incurring significant immunogenecity or biological inactivation. Apart from
these advantages the pharmaceutical companies recognize the possibility of repattening
successfull drugs by appling the concepts and techniques of controlled drug
delivery system coupled with the increased expense in bringing new drug moiety
to the market(1).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 (2).


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
drugs across this layer.  The method to circumvent this is to engineer
the drugs be both water-soluble and lipid soluble.  The best mixture is
about fifty percent of the drug being each.   This is because “Lipid-soluble
substances readily pass through the intercellular lipid bi-layers of the cell
membranes whereas water-soluble drugs are able to pass through the skin because
of hydrated intracellular proteins”.  Using drugs engineered in this manner,
much more rapid and useful drug delivery is possible.(3)


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.(4)


TRANSDERMAL DRUG DELIVERY SYSTEM


Transdermal drug delivery system are topicaly administered medicaments
in the form of patches that deliver drugs for systemic effects at a predetermined
and controlled rate.(1)


A transdermal drug delivery device, which may be of an active or a passive
design, is a device which provides an alternative route for administering medication.
These devices allow for pharmaceuticals to be delivered across the skin barrier
(5). In theory, transdermal patches work very simply.  A drug is applied
in a relatively high dosage to the inside of a patch, which is worn on the skin
for an extended period of time.  Through a diffusion process, the drug
enters the bloodstream directly through the skin.  Since there is high
concentration on the patch and low concentration in the blood, the drug will
keep diffusing into the blood for a long period of time, maintaining the constant
concentration of drug in the blood flow.(3)


This approach to drug delivery offers many advantages over traditional
methods. As a substitute for the oral route, transdermal drug delivery enables
the avoidance of gastrointestinal absorption, with its associated pitfalls of
enzymatic and pH associated deactivation. This method also allows for reduced
pharmacological dosaging due to the shortened metabolization pathway of the
transdermal route versus the gastrointestinal pathway. The patch also permits
constant dosing rather than the peaks and valleys in medication level associated
with orally administered medications. Multi-day therapy with a single application,
rapid notification of medication in the event of emergency, as well as the capacity
to terminate drug effects rapidly via patch removal, are all further advantages
of this route.(6)  


However this system has its own limitations in which the drug that require
high blood levels cannot be administered and may even cause irritation or sensitization
of the skin.the adhesives may not adhere well to all types of skin and may be
uncomfortable to wear. Along with these limitations the high cost of the product
is also a major drawback for the wide acceptance of this product.(5)


PROPERTIES THAT INFLUENCE TRANSDERMAL DELIVERY


§ Release of the medicament from the vehicle.


§ Penetration through the skin barrier.


§  Activation of the pharmacological response.(7)


KINETICS OF TRANSDERMAL PERMEATION


Knowledge of skin permeation kinetics is vital to the successful development
of transdermal therapeutic systems. Transdermal permeation of a drug involves
the following steps:


      1. Sorption by stratum corneum.


      2. Penetration of drug through viable
epidermis.


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


This permeation can be possible only if the drug possesses certain physiochemical
properties.


The rate of permeation across the skin is given by:


              dQ   


            ------    =       Ps ( Cd – Cr )              .. ……………………….. (1)  


               dt


where Cd and Cr are the concentration of the skin penetrant
in the donor compartment i.e. on the surface of stratum corneum and in the receptor
compartment i.e. body respectively. Ps is the overall permeability coefficient
of the skin tissue to the penetrant. This permeability coefficient is given
by the relationship:


                 
                        Ks
Dss


              Ps     =       ----------------------


                                             hs     


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


                
dQ


               -------     =      Ps Cd


                  dt


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


Since Rr >> Ra , the drug concentration on the
skin surface Cd is maintained at a level equal to or greater than
the equilibrium solubility of the drug in the stratum corneum Cs
.i.e. Cd>>Cs. Therefore a maximum rate of skin permeation
is obtained and is given by the equation:


    (dQ/dt)m    =    PsCs


From the above equation it can be seen that the maximum rate of
skin permeation depends upon the skin permeability coefficient Ps
and is equilibrium solubility in the stratum corneum Cs. Thus skin
permeation appears to be stratum corneum limited. (8)


Basic Components of Transdermal Drug Delivery Systems


 The components of transdermal devices include:


1. Polymer matrix or matrices.


2.  The drug


3.  Permeation enhancers


4. Other excipients


 


1.Polymer Matrix


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


Possible useful polymers for transdermal devices are:


a) Natural Polymers:


e.g. Cellulose derivatives, Zein, Gelatin, Shellac, Waxes, Proteins, Gums and their derivatives, Natural rubber, Starch etc.


b) Synthetic Elastomers:


e.g. Polybutadieine, Hydrin rubber, Polysiloxane, Silicone rubber, Nitrile, Acrylonitrile, Butyl rubber, Styrenebutadieine rubber, Neoprene etc.


c) Synthetic Polymers:


e.g. Polyvinyl alcohol, Polyvinyl chloride, Polyethylene, Polypropylene, Polyacrylate, Polyamide, Polyurea, Polyvinylpyrrolidone, Polymethylmethacrylate, Epoxy etc.


 2.Drug


 For successfully developing a transdermal drug delivery system,
the drug should be chosen with great care. The following are some of the desirable
properties of a drug for transdermal delivery.


Physicochemical properties


1. The drug should have a molecular weight less than approximately 1000 daltons.


2. The drug should have affinity for both – lipophilic and hydrophilic phases. Extreme partitioning characteristics are not conducive to successful drug delivery via the skin.


3. The drug should have low melting point.


Along with these propertiesthe drug should be potent, having short half life and be non irritating.


3.Permeation Enhancers


 These are compounds which promote skin permeability by altering
the skin as a barrier to the flux of a desired penetrant.


These may conveniently be classified under the following main headings:


 a) Solvents


These compounds increase penetration possibly by swallowing the polar pathway and/or by fluidizing lipids. Examples include water alcohols – methanol and ethanol; alkyl methyl sulfoxides – dimethyl sulfoxide, alkyl homologs of methyl sulfoxide dimethyl acetamide and dimethyl formamide ; pyrrolidones – 2 pyrrolidone, N-methyl, 2-purrolidone; laurocapram (Azone), miscellaneous solvents – propylene glycol, glycerol, silicone fluids, isopropyl palmitate.


 b) Surfactants


These compounds are proposed to enhance polar pathway transport, especially of hydrophilic drugs.The ability of a surfactant to alter penetration is a function of the polar head group and the hydrocarbon chain length.


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

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

Bile Salts: e.g. Sodium ms taurocholate, Sodium deoxycholate,
Sodium tauroglycocholate.

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Biary system: These systems apparently open up the heterogeneous multilaminate pathway as well as the continuous pathways.e.g. Propylene glycol-oleic acid and 1, 4-butane diol-linoleic acid.


c) Miscellaneous chemicals


These include urea, a hydrating and keratolytic agent; N, N-dimethyl-m-toluamide; calcium thioglycolate; anticholinergic agents.


 Some potential permeation enhancers have recently been described but the available data on their effectiveness sparse. These include eucalyptol, di-o-methyl-ß-cyclodextrin and soyabean casein.(8)


4.Other Excipients  


 a) Adhesives:


The fastening of all transdermal devices to the skin has so far been done by
usinga pressure sensitive adhesive which can be positioned on the face of the
device or in the back of the device and extending peripherally. Both adhesive
systems should fulfill the following criteria


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


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


(iii) Should not irritate or sensitize the skin.


The face adhesive system should also fulfill the following criteria.


(i)Physical and chemical compatibility with the drug, excipients and enhancers
of the device of which it is a part.


(ii) Permeation of drug should not be affected.


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


b) Backing membrane:


Backing membranes are flexible and they provide a good bond to the drug reservoir, prevent drug from leaving the dosage form through the top, and accept printing. It is impermeable substance that protects the product during use on the skin e.g. metallic plastic laminate, plastic backing with absorbent pad and occlusive base plate (aluminium foil), adhesive foam pad (flexible polyurethane) with occlusive base plate (aluminium foil disc) etc.(9)


Desirable features for transdermal patches


Composition relatively invariant in use.


System size reasonable.


Defined site for application.


Application technique highly reproducible.


Delivery is (typically) zero order.


Delivery is efficient.(10)


TYPES OF TRANSDERMAL PATCHES


 Four Major Transdermal Systems


1. Single-layer Drug-in-Adhesive 


ImageImage



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.(11)

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


                                          Cr


           dQ/dT  =    ---------------------------        


                                    1/Pm + 1/Pa


 


wher Cr is the drug concentration in the reservoir compartment and Pa and P m are the permeability coefficients of the adhesive layer and the rate controlling membrane , Pm is the sum of permeability coefficients simultaneous penetrations across the pores and the polymeric material. Pm and Pa , respectively, are defined as follows.


                     
 Km/r . Dm


   Pm =     _____________


                        hm


               


                       Ka/m . Da


 Pa =      _____________


                          ha 


 


where Km/r and Ka/m are the partition coefficients for the interfacial partitioning of drug from the reservoir to the membrane and from the membrane to adhesive respectively; Dm and Da are the diffusion coefficients in the rate controlling membrane and adhesive layer, respectively; and hm and ha are the thicknesses of the rate controlling membrane and adhesive layer, respectively.(8,9)


2.  Multi-layer Drug-in-Adhesive 


ImageImage                   
 


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.(11)


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


                     Ka/r . Da


dQ/dt =  ------------------------ Cr


                            ha


where Ka/r is the partition coefficient for the interfacial partitioning
of the drug from the reservoir layer to adhesive layer.(1,9)


3. Drug Reservoir-in-Adhesive


ImageImage


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.(11)


The rate of drug release from this drug reservoir gradient controlled system
is given by:


                                       Ka/r . Da


                  dQ/dt =  --------------------- A ( ha )


                                          ha ( t )


 


In the above equation, the thickness of the adhesive layer for drug molecules
to diffuse through increases with time ha (t). To compensate for this time dependent
increase in the diffusional path due to the depletion of drug dose by release,
the drug loading level is also  increased with the thickness of diffusional
path A (ha).(7,8)


4. Drug Matrix-in-Adhesive


ImageImage


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.
(11).


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.(8,9).


Transdermal Market


The market for transdermal products has been in a significant upward trend
that is likely to continue for the foreseeable future. An increasing number
of TDD products continue to deliver real therapeutic benefit to patients around
the world. More than 35 TDD products have now been approved for sale in the
US, and approximately 16 active ingredients are approved for use in TDD products
globally.(12). The table 1 gives detail information of the different drugs which
are administered by this route and the common names by which they are marketed;
it also gives the conditions for which the individual system is used.(13).   


TABLE - 1

































































































































Product name


Drug


Manufacturer


Indication


Alora


Estradiol


TheraTech/Proctol and Gamble


Postmenstrual syndrome


Androderm


Testosterone


TheraTech/GlaxoSmithKline


Hypogonadism in males


Catapres-TTS


Clonidine


Alza/Boehinger Ingelheim


Hypertension


Climaderm


Estradiol


Ethical Holdings/Wyeth-Ayerest


Postmenstrual syndrome


Climara


Estradiol


3M Pharmaceuticals/Berlex Labs


Postmenstrual syndrome


CombiPatch


Estradiol/Norethindrone


Noven , Inc./Aventis


Hormone replacement therapy


Deponit


Nitroglycerin


Schwarz-Pharma


Angina pectoris


Duragesic


Fentanyl


Alza/Janssen Pharmaceutica


Moderate/severe pain


Estraderm


Estradiol


Alza/Norvatis


Postmenstrual syndrome


Fematrix


Estrogen


Ethical Holdings/Solvay Healthcare Ltd.


Postmenstrual syndrome


FemPatch


Estradiol


Parke-Davis


Postmenstrual syndrome


Habitraol


Nicotine


Novartis


Smoking cessation


Minitran


Nitroglycerin


3M Pharmaceuticals


Angina pectoris


Nicoderm


Nicotine


Alza/GlaxoSmithKline


Smoking cessation


Nicotrol


Nicotine


Cygnus Inc./McNeil Consumer Products, Ltd.


Smoking cessation


Nitrodisc


Nitroglycerin


Roberts Pharmaceuticals


Angina pectoris


Nitro-dur


Nitroglycerin


Key Pharmaceuticals


Angina pectoris


Nuvelle TS


Estrogen/Progesterone


Ethical Holdings/Schering


Hormone replacement therapy


Ortho-Evra


Norelgestromin/estradiol


Ortho-McNeil Pharmaceuticals


Birth control


Prostep


Nicotine


Elan Corp./Lederle Labs


Smoking cessation


Testoderm TTS


Testosterone


Alza


Hypogonadism in males


Transderm Scop


Scopolamine


Alza/Norvatis


Motion sickness


Transderm Nitro


Nitroglycerin


Alza/Norvatis


Angina pectoris


Vivelle


Estradiol


Noven Pharmaceuticals/Norvatis


Postmenstrual syndrome                   


The pie diagram given below shows that Fentanyl and nitroglycerine are the
drugs most popularly marketed using transdermal patches.


ADVANCE DEVELOPMENT IN TDDS


Image


Drug in adhesive technology has become the preferred system for passive transdermal delivery, two areas of formulation research are focused on adhesives and excipients. Adhesive research focuses on customizing the adhesive to improve skin adhesion over the wear period, improve drug stability and solubility, reduce lag time, and increase the rate of delivery. Because a one-size-fits-all adhesive does not exist that can accommodate all drug and formulation chemistries, customizing the adhesive chemistry allows the transdermal formulator to optimize the performance of the transdermal patch.(12)


A rich area of research over the past 10 to 15 years has been focused
on developing transdermal technologies that utilize mechanical energy to increase
the drug flux across the skin by either altering the skin barrier (primarily
the stratum corneum) or increasing the energy of the drug molecules. These so-called
“active” transdermal technologies include iontophoresis (which uses low voltage
electrical current to drive charged drugs through the skin), electroporation
(which uses short electrical pulses of high voltage to create transient aqueous
pores in the skin), sonophoresis (which uses low frequency ultrasonic energy
to disrupt the stratum corneum), and thermal energy (which uses heat to make
the skin more permeable and to increase the energy of drug molecules). Even
magnetic energy, coined magnetophoresis, has been investigated as a means to
increase drug flux across the skin.(12)


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.


REFERENCES



  1. Chien, YW, Novel drug delivery systems, Drugs and the Pharmaceutical Sciences,
    Vol.50, Marcel Dekker, New York, NY;1992;797
  2. 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.
  3. Transdermal drug delivery
    system/introduction

  4. Aulton.M.E, Pharmaceutics; The science of dosage form design, second edition, Churchill Livingston, Harcourt publishers-2002.
  5. Ansel.H.C, Loyd.A.V, Popovich.N.G, Pharmaceutical dosage forms and drug delivery systems, Seventh edition, Lippincott Williams and Willkins publication.
  6. Brahmankar.D.M, Jaiswal.S.B, Biopharmaceutics and pharmacokinetics A Teatise. Vallabh Prakashan, Delhi1995,335-371.
  7. Banker, G. S and Rhodes, C. T  Modern pharmaceutics, third edition, New York, Marcel Dekker, inc,. 1990.
  8. Jain.N.K, Controlled and novel drug delivery ,first edition, CBS publishers and distributors, New Delhi.1997.
  9. Mathiowitz.Z.E, Chickering.D.E, Lehr.C.M, Bioadhesive drug delivery systems; fundamentals,novel approaches and development, Marcel Dekker, inc New York . Basel
  10. www.Controlled release drug delivery systems.com
  11. 3M World Wide, 3M Drug delivery system, Transdermal patches, www.3Mworldwide.com
  12. Ryan D. Gordon, and Tim A. Peterson, transdermal drug delivery , drug delivery
    technology, www.drugdeliverytechnology.com

  13. www.biomed.brown.edu/Courses/BI108.

About author

Girish Chopda


MAEER’s Maharashtra Institute of Pharmacy,  S No 124, MIT Campus, 
Pune 411 038,  M.S., India.  Email: girishchops7@yahoo.com

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