Transdermal drug delivery system

Transdermal Drug Delivery
System
Dr. Prashant L. Pingale
Associate Professor, Dept. of Pharmaceutics
GES’s Sir Dr. M. S. Gosavi College of Pharm. Edu. & Research,
Nashik-422005, INDIA

Topics to be covered…
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 Introduction,
 History,
 Advantage & Disadvantage of TDDS
 General considerations in TDDS,
 Skin & layers in TDDS,
 Mechanism of Transdermal delivery,
 Factors influencing transdermal permeation,
 Basic components & formulation of transdermal patches,
 Considerations while formulation of TDDS,
 Types of TDDS,
 Evaluation of TDDS,
 Marketed products.

Transdermal Drug Delivery System
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 Delivery of drug across the skin into systemic circulation
 Relative accessibility of skin thereby diffusing the drug
molecules thr’ skin into the systemic circulation for
distribution to illicit its pharmacological action.
 Example in market include: hormone replace therapy,
smoking cessation and pain management.

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 Continuous intravenous infusion at a programmed rate has
been recognized as a superior mode of drug delivery which
bypasses the hepatic first pass elimination as well as
maintains a constant, prolonged and therapeutically effective
drug level in the body.
 Recently, continuous transdermal drug administration through
intact skin has been an projected to be as beneficial as
intravenous drug infusion without its potential hazards.

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 Adhesive patch containing drug which passively diffuses through
the skin, usually small molecules or fat-soluble
 Currently available drugs include:
 Contraceptives Nicotine Estrogen
 Testosterone Scopolamine Nitroglycerine
 Newer ‘active’ technologies allow for delivery of larger molecules
such as proteins
 Several external driving forces such as ultrasound, heat, and electric
fields can be applied to the skin, causing transient pores to facilitate
active drug transport.

History of TDDS
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 Earlier eras by the use of certain plasters and ointments. The mustard
plaster, applied as a home remedy for severe chest congestion.
 Powdered mustard seed (Brassica nigra: Brassicaceae) was mixed
with warm water, and the resulting paste was spread on a strip of
flannel, which was applied to the patient’s chest with a cloth binding
wrapped around the body to hold the plaster in place.
 The moisture and body warmth activated an enzyme (myrosin) in the
mustard that hydrolyzed a glycoside (sinigrin), causing the release of
the pungent active ingredient allyl isothio-cyanate.

Mechanism of mustard patch
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 This substance possesses the qualifications listed above for
transdermal absorption.
 It is a low MW liquid (90 Da), lipophilic, effective at low dosage.
 The flannel: impermeable backing & mustard paste: reservoir.
Continuous enzymatic action released the active substance over a
period of hours, until the plaster was removed. Commercially
manufactured mustard plasters were sold at pharmacies.

History of TDDS
8
 The history of plasters has been traced back to olden days.
 In addition to mustard plasters, several other plasters were
recognized in early 20th century editions of the United States
Pharmacopeia (USP) and National Formulary (NF).
 At one time, Belladonna Plaster, containing 0.25–0.30% of
belladonna root alkaloids, was believed to act transdermally as an
analgesic.
 Belladonna: BS: Atropa belladonna , F: Brassicaceae
CC: Scopalamine

Advantages
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 Avoids gastrointestinal drug absorption difficulties caused by
gastrointestinal pH, enzymatic activity, drug interactions with food,
drinks, or other orally administered drugs.
 Substitutes for oral administration of medication when that routes is
unsuitable, as in instances of vomiting and/or diarrhea.
 Avoids first-pass effect, that is, the initial pass of a drug substance
through the systemic and portal circulation following gastrointestinal
absorption (thereby possibly avoiding the drug’s deactivation by
digestive and liver enzymes).
 Avoids the risks and inconveniences of parenteral therapy and the
variable absorption and metabolism associated with oral therapy.

Advantages
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 Provides the capacity for multiday therapy with a single application,
thereby improving patient compliance over use of other dosage forms
requiring more frequent dose administration.
 Extends the activity of drugs having short half-life through the reservoir
of drug present in the therapeutic delivery system and its controlled
release characteristics.
 Provides capacity to terminate drug effect rapidly (if clinically desired)
by removal of drug application from the surface of the skin.
 Provides ease of rapid identification of the medication in emergencies
(e.g. non responsive, unconscious or comatose patient).

Disadvantages
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 Unsuitable for drugs that irritate or sensitize the skin.
 Only relative potent drugs are suitable candidates (due to the
natural limits of drug entry imposed by the skin’s
impermeability).
 Drug that require high blood levels cannot be administered
 Adhesive may not adhere well to all types of skin
 Uncomfortable to wear
 May not be economical

General Considerations in the use of TDDS
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The site selected for application should be clean, dry and hairless
(but not shaved)
 Example: nitroglycerin - chest; estradiol - buttocks or abdomen;
scopolamine - behind the ear; nicotine – upper trunk or upper outer arm.
The transdermal patch should not be applied to skin that is oily,
irritated, cut, or abraded. This is to assure the intended amount and
rate of transdermal drug delivery and absorption.
The patch should be removed from its protective package, being
careful not to tear or cut.

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The patch should be worn for the period of time stated in the product’s
instructions. Following period, the patch should be removed and a fresh
patch applied as directed.
Patches generally may be left on when showering, bathing, or
swimming. Should a patch premature dislodge, an attempt may be made
to reapply it, or it may be replaced with a fresh patch-- the latter being
worn for a full time period before it is replaced.
The patient should be instructed to cleanse the hands thoroughly before
and after applying the patch. Care should be taken not to rub the eyes or
touch the mouth during handling the patch.
If irritation results, patient should seek re-evaluation.
General Considerations in the use of TDDS

Factors influence the permeation of drugs
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 Nature of the drug itself
 Nature of the vehicle
 The nature of the skin
 Presence of moisture

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 Drug concentration is an important factor
 Most drug is absorbed through percutaneous absorption when the drug
substance is applied to a larger surface area.
 The drug should have a greater physicochemical attraction to the skin than to
the vehicle in which it is presented in order for the drug to leave the vehicle in
favor the skin.
 Drug absorption appears to be enhanced from vehicles that easily cover the
skin surface, mix readily with the sebum, and bring the drug into contact with
the tissue cells for absorption.

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 Vehicles that increase the hydration of the skin generally favor the
percutaneous absorption of drugs.
 The amount of rubbing in or inunctions of the topical application will have
a bearing on the amount of drug absorbed, the longer the period of
inunction, the greater the absorption.
 Percutaneous absorption appears to be greater when the drug is applied to
skin with a thin horny layer than with one that is thick.
 The longer the period of time the medicated application is permitted to
remain in contact with the skin, the greater will be the absorption.
 Multiple-application dosing rather than single bolus applications can
increase drug absorption

Skin & layers in TDDS
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 For TDDS, drug must pass through two sub layers of
the epidermis i.e. stratum corneum and viable
epidermis to reach dermis
 Three distinct layers of the skin:
 stratum corneum (15 m thick)
 viable epidermis (150 m thick)
 papillary layer of dermis (100 to 200 m thick)

Process of transdermal permeation
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Mechanism of Transdermal DDS
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 There are two important layers in skin: the dermis and epidermis.
 The outermost layer, epidermis (approx. 100 to 150 μm thick), has no
blood flow & includes a layer within it known as stratum corneum.
 This is the layer most important to transdermal delivery as its
composition allows it to keep water within body & foreign subs. out.
 Below 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.

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 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 avoid this is to engineer 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”.

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 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.

Basic Components of TDDS
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 Polymer matrix or matrices.
 The drug
 Permeation enhancers
 Other excipients

Polymer matrix in TDDS
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 Natural Polymers:
 e.g. Cellulose derivatives, Zein, Gelatin, Shellac, Waxes, Proteins, Gums
and their derivatives, Natural rubber, Starch etc.
 Synthetic Elastomers:
 e.g. Polybutadieine, Hydrin rubber, Polysiloxane, Silicone rubber, Nitrile,
Acrylonitrile, Butyl rubber, Styrenebutadieine rubber, Neoprene
 Synthetic Polymers:
 e.g. PVA, PVC, PE, PP, Polyacrylate, Polyamide, Polyurea, PVP,
Polymethylmethacrylate, Epoxy etc.

Drug
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 The drug should have a molecular weight less than approximately
1000 daltons.
 The drug should have affinity for both – lipophilic and hydrophilic
phases. Extreme partitioning characteristics are not conducive to
successful drug delivery via the skin.
 The drug should have low melting point.
 The drug should be potent.
 Should have short half life and be non irritating.

Permeation Enhancers
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 Solvents:
 These compounds increase penetration possibly by swallowing the polar
pathway and/or by fluidizing lipids.
 Examples: water alcohols – methanol and ethanol; alkyl methyl sulfoxides
– dimethyl sulfoxides, 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.

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 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 taurocholate, Sodium deoxycholate,
Sodium tauroglycocholate.

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 Miscellaneous chemicals:
 E.g. urea, a hydrating and keratolytic agent,
 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.

Other Excipients
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 Adhesives:
 The fastening of all transdermal devices to the skin has so
far been done by using a 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:
 Should adhere to the skin aggressively, should be easily removed.
 Should not leave an unwashable residue on the skin.
 Should not irritate or sensitize the skin.

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 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.

Types of transdermal patches
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 Single-layer drug-in-adhesive patch
 Multi-layer drug-in adhesive patch
 Reservoir
 Matrix
 Vapour patches

TYPES OF TRANSDERMAL PATCHES
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 Single-layer Drug-in-Adhesive:
 The adhesive layer of this system contains the drug. In this type of
patch the adhesive layer not only serves to adhere the various
layers together, along with the entire system to the skin, but is also
responsible for the releasing of the drug. The adhesive layer is
surrounded by a temporary liner and a backing.

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 Multi-layer drug-in adhesive patch:
 both adhesive layers are also responsible for the releasing of drug.
 One of the layers is for immediate release of the drug and other layer
is for control release of drug from the reservoir.
 This patch also has a temporary liner-layer & a permanent backing.

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 Reservoir:
 reservoir transdermal system has a separate drug layer.
 The drug layer is a liquid compartment containing a drug
solution or suspension separated by the adhesive layer.
 This patch is also backed by the backing layer.
 In this type of system the rate of release is zero order.

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 Matrix:
 The Matrix system has a drug layer of a semisolid matrix
containing a drug solution or suspension. The adhesive layer
in this patch surrounds the drug layer partially overlaying it.

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 Vapour Patch:
 Adhesive layer not only serves to adhere the various layers
together but also to release vapour.
 The vapour patches are new in the market and they release
essential oils for up to 6 hours.
 The vapour patches release essential oils and are used in cases
of decongestion mainly.
 Other vapour patches in the market are controller vapour
patches that improve the quality of sleep.
 Vapour patches that reduce the quantity of cigarettes that one
smokes in a month are also available in the market.

Mechanisms of Transdermal Patches
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 Matrix type
 Reservoir type
 Membrane matrix hybrid
 Micro reservoir type
 Drug in adhesive type

Matrix type transdermal patches
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 Advantages:
 Drug reservoir is prepared by dissolving the drug and polymer in a
common solvent.
 The insoluble drug should be homogenously dispersed in hydrophilic
or lipophilic polymer.
 absence of dose dumping, direct exposure of polymeric matrix to the
skin and no interference of adhesive.
 The required quantity of plasticizer like dibutylpthalate,
triethylcitrate, PEG or PG and permeation enhancer is then added
and mixed properly.

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 Commonly used polymers for matrix are cross linked PEG, eudragits,
EC, PVP & HPMC.
 The medicated polymer formed is then molded into rings with defined
surface area and controlled thickness over the mercury on horizontal
surface followed by solvent evaporation at an elevated temperature.
 The film formed is then separated from the rings, which is then mounted
onto an occlusive base plate in a compartment fabricated from a drug
impermeable backing.

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 Adhesive polymer is then spread along the circumference of the film.
 Dispersion of drug particles in polymer matrix can be accomplished
by either homogenously mixing the finely ground drug particles with
a liquid polymer or a highly viscous base polymer followed by cross
linking of polymer chains or homogenously blending drug solids with
a rubbery polymer at an elevated temperature.
 Marketed product: Nitro-Dur®: Nitroglycerine: Angina pectoris.

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Reservoir Type Transdermal Patches
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 The drug reservoir is made of a homogenous dispersion of
drug particles suspended in an unleachable viscous liquid medium
(e.g. silicon fluids) to form a paste like suspension or gel or a clear
solution of drug in a releasable solvent (e. g. ethanol). The drug
reservoir formed is sandwiched between a rate controlling
membrane and backing laminate.
 The rate controlling membrane can be nonporous so that the drug is
released by diffusing directly through the material, or the material
may contain fluid filled micropores in which case drug may
additionally diffuse through fluid, thus filling the pores.

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 Mostly EVA, EC, silicon rubber and polyurethanes are used to
prepare rate controlling membranes.
 EVA is used most frequently to prepare rate controlling membrane in
TDDS because it allows the membrane permeability to be altered by
adjusting vinyl acetate content of polymer.
 Rate controlling membrane may be prepared by solvent evaporation
method or compression method.

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 In case of solvent evaporation method, polymer is dissolved in
solvent with or without plasticizer. Then the solution is poured
on the horizontal surface and left for evaporation of solvent in
order to obtain a thin film.
Drug Rate controlling membrane
Polymer Solvent Plasticizer
Scopolamine EVA Toluene
Nicotine EC
Chloroform and
dichloromethane
Scopolamine EC Methylene chloride

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 Marketed preparations:
 Duragesic®: Fentanyl, a potent opioid, one patch may
provide 72 hours of pain relief.
 Estradem®: Estradiol: female sex hormone
 Androderm®: Testosterone: sex hormone

The reservoir type of patch
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The protective peel strip is removed prior to applying
the patch to skin.

Membrane matrix hybrid type patch
50
 This is the modification of reservoir type transdermal patch.
 The liquid formulation of the drug reservoir is replaced with a solid
polymer matrix (e.g. polyisobutylene) which is sandwiched
between rate controlling membrane and backing laminate.
 Marketed preparations:
 Catapress®: clonidine: antihypertensive agent.
 TransdermScop®: scopolamine: anticholinergic used in motion
sickness

Micro reservoir type transdermal patch
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 The drug reservoir is formed by suspending the drug solids in an
aqueous solution of water miscible drug solubilizer e.g. PEG.
 The drug suspension is homogenously dispersed by a high shear
mechanical force in lipophilic polymer, forming thousands of
unleachable microscopic drug reservoirs (micro reservoirs).
 The dispersion is quickly stabilized by immediately cross linking
the polymer chains in-situ which produces a medicated polymer
disc of a specific area and fixed thickness.

Micro reservoir type transdermal patch
52
 Occlusive base plate mounted between the medicated disc and
adhesive form backing, prevents the loss of drug through the
backing membrane.
 Marketed preparations: Nitrodisc®: Nitroglycerine

Drug in adhesive type transdermal patch
53
 The drug & other selected excipients, if any, are directly incorporated into the
organic solvent based pressure sensitive adhesive solution, mixed, cast as a thin
film and dried to evaporate the solvents, leaving a dried adhesive matrix film
containing the drug and excipients.
 This drug in adhesive matrix is sandwiched betn release liner & backing layer.
Drug -in -adhesive patch may be single layer or multi layer. The multi layer
system is different from single layer in that it adds another layer of drug-in-
adhesive, usually separated by a membrane.
 Marketed preparations: Climara®: Estradiol: female sex hormone
 Nicotrol® : Nicotine replacement therapy
 Deponit®: Nitroglycerine

Evaluation of Transdermal Patches
 Transdermal patches have been developed to improve clinical
efficacy of the drug and to enhance patient compliance by
delivering smaller amount of drug at a predetermined rate.
 transdermal dosage forms and can be classified into following
types:
 Physicochemical evaluation
 In vitro evaluation
 In vivo evaluation

Physicochemical Evaluation
 Thickness
 Uniformity of weight
 Drug content determination
 Content uniformity test
 Moisture content
 Moisture Uptake
 Flatness
 Folding Endurance
 Water vapor transmission
studies (WVT)
 Microscopic studies
 Adhesive studies

 Thickness: The thickness of transdermal film is determined by
traveling microscope, dial gauge, screw gauge or micrometer at
different points of the film.
 Uniformity of weight: Weight variation is studied by
individually weighing 10 randomly selected patches and
calculating the average weight. The individual weight should not
deviate significantly from the average weight.

 Drug content determination: An accurately weighed portion of
film (about 100 mg) is dissolved in 100 mL of suitable solvent in
which drug is soluble and then the solution is shaken
continuously for 24 h in shaker incubator. Then the whole
solution is sonicated. After sonication and subsequent filtration,
drug in solution is estimated spectrophotometrically by
appropriate dilution.

 Content uniformity test: 10 patches are selected and content is
determined for individual patches. If 9 out of 10 patches have
content between 85% to 115% of the specified value and one has
content not less than 75% to 125% of the specified value, then
transdermal patches pass the test of content uniformity. But if 3
patches have content in the range of 75% to 125%, then
additional 20 patches are tested for drug content. If these 20
patches have range from 85% to 115%, then the transdermal
patches pass the test.

 Moisture content: The prepared films are weighed individually
and kept in a desiccators containing calcium chloride at room
temperature for 24 h. The films are weighed again after a
specified interval until they show a constant weight. The percent
moisture content is calculated using following formula.
 % Moisture content = Final weight – Initial weight X 100
Initial weight

 Moisture Uptake: Weighed films are kept in a desiccator at
room temperature for 24 h. These are then taken out and
exposed to 84% relative humidity using saturated solution of
Potassium chloride in a desiccator until a constant weight is
achieved. % moisture uptake is calculated as given below.
 % moisture uptake = Final weight – Initial weight X 100
Initial weight

 Flatness: A transdermal patch should possess a smooth surface and
should not constrict with time. This can be demonstrated with flatness
study. For flatness determination, one strip is cut from the centre and
two from each side of patches. The length of each strip is measured and
variation in length is measured by determining percent constriction.
Zero percent constriction is equivalent to 100 percent flatness.
 % constriction = I1 – I2 / I1 X 100
 I2 = Final length of each strip
 I1 = Initial length of each strip

 Folding Endurance: Evaluation of folding endurance involves
determining the folding capacity of the films subjected to
frequent extreme conditions of folding.
 Folding endurance is determined by repeatedly folding the film
at the same place until it break. The number of times the films
could be folded at the same place without breaking is folding
endurance value.

 Water vapor transmission studies (WVT):
 Weighed 1 gm of CaCl2 and placed it in previously dried empty vials
having equal diameter. The polymer films were pasted over the edge
with the help of adhesive like silicon adhesive grease and the adhesive
was allowed to set for 5 minutes. Then, the vials were accurately
weighed and placed in humidity chamber maintained at 65-70 % RH.
The vials were again weighed at the end of every 1st day, 2nd day, 3rd
day up to 7 consecutive days and an increase in weight was considered
as a quantitative measure of moisture transmitted through the patch.

 In second methods: desiccators were used to place vials, in which
200 mL of saturated sodium bromide and saturated potassium
chloride solution were placed. The desiccators were tightly closed
and humidity inside the desiccator was measured by using
hygrometer. The weighed vials were then placed in desiccator and
procedure was repeated.
 WVT = W/ ST
 W is the increase in weight in 24 h; S is area of film exposed (cm2);
T is exposure time.

 Microscopic studies: Distribution of drug and polymer in the
film can be studied using scanning electron microscope. For
this study, the sections of each sample are cut and then mounted
onto stubs using double sided adhesive tape. The sections are
then coated with gold palladium alloy using fine coat ion sputter
to render them electrically conductive. Then the sections are
examined under scanning electron microscope.

 Adhesive studies: The therapeutic performance of TDDS can be
affected by the quality of contact between the patch and the skin.
 The adhesion of a TDDS to the skin is obtained by using pressure
sensitive adhesives: adhesives capable of bonding to surfaces with
the application of light pressure.
 The adhesive properties of a TDDS can be characterized by
considering the following factors:
 Peel Adhesion properties &
 Tack properties

 Peel Adhesion properties: It is the force required to remove
adhesive coating from test substrate. It is tested by measuring the
force required to pull a single coated tape, applied to substrate at
180° angle. The test is passed if there is no residue on the substrate.
 Tack properties: It is the ability of the polymer to adhere to
substrate with little contact pressure. Tack is dependent on
molecular weight and composition of polymer as well as on the use
of tackifying resins in polymer.

 Thumb tack test: The force required to remove thumb from adhesive is a
measure of tack.
 Rolling ball test: This test involves measurement of the distance that
stainless steel ball travels along an upward facing adhesive. The less
tacky the adhesive, the further the ball will travel.
 Quick stick (Peel tack) test: The peel force required to break the bond
between an adhesive and substrate is measured by pulling the tape away
from the substrate at 90◦ at the speed of 12 inch/min.
 Probe tack test: Force required to pull a probe away from an adhesive at
a fixed rate is recorded as tack.

In vitro release studies
 Drug release mechanisms and kinetics are two characteristics of
the dosage forms which play an important role in describing the
drug dissolution profile from a controlled release dosage forms
and hence their in vivo performance.
 A number of mathematical model have been developed to
describe the drug dissolution kinetics from controlled release drug
delivery system e.g., Higuchi, First order, Zero order and Peppas
and Korsenmeyer model.
 The dissolution data is fitted to these models and the best fit is
obtained to describe the release mechanism of the drug.

Methods for determination of drug
release
 The Paddle over Disc
 The Cylinder modified USP Basket
 The reciprocating disc
 Diffusion Cells e.g. Franz Diffusion Cell and its modification
Keshary- Chien Cell

Methods for determination of drug release
 The Paddle over Disc:
 USP apparatus 5/ PhEur 2.9.4.1
 This method is identical to the USP paddle dissolution apparatus, except
that the transdermal system is attached to a disc or cell resting at the
bottom of the vessel which contains medium at 32 ±5°C.
 The Cylinder modified USP Basket:
 USP apparatus 6 / PhEur 2.9.4.3
 This method is similar to the USP basket type dissolution apparatus,
except that the system is attached to the surface of a hollow cylinder
immersed in medium at 32 ±5°C.

USP apparatus 6- Rotating hollow cylinder
USP apparatus 5- Glass disc

Methods for determination of drug
release
 The reciprocating disc:
 USP apparatus 7.
 In this method patches attached to holders are oscillated in small volumes
of medium, allowing the apparatus to be useful for systems delivering
low concentration of drug.
 In addition paddle over extraction cell method (PhEur 2.9.4.2) may be
used.

 12 row system,
 The medium is changed by advancing the apparatus to the next
row of tubes containing fresh medium
USP apparatus 7

 Diffusion Cells e.g. Franz Diffusion Cell and its modification
Keshary- Chien Cell:
 In this method transdermal system is placed in between receptor and donor
compartment of the diffusion cell.
 The transdermal system faces the receptor compartment in which receptor fluid
i.e., buffer is placed.
 The agitation speed and temperature are kept constant.
 The whole assembly is kept on magnetic stirrer and solution in the receiver
compartment is constantly and continuously stirred throughout the experiment
using magnetic beads.
 At predetermined time intervals, the receptor fluid is removed for analysis and
is replaced with an equal volume of fresh receptor fluid.
 The concentration of drug is determined spectrophotometrically.

In vitro permeation studies
 The amount of drug available for absorption to the systemic pool is
greatly dependent on drug released from the polymeric transdermal
films. The drug reached at skin surface is then passed to the dermal
microcirculation by penetration through cells of epidermis, between
the cells of epidermis through skin appendages.
 Permeation studies are performed by placing the fabricated
transdermal patch with rat skin or synthetic membrane in between
receptor and donor compartment in a vertical diffusion cell such as
franz diffusion cell or keshary-chien diffusion cell.

 The transdermal system is applied to the hydrophilic side of the
membrane and then mounted in the diffusion cell with lipophilic side
in contact with receptor fluid. The receiver compartment is
maintained at specific temperature (usually 32±5°C for skin) and is
continuously stirred at a constant rate.
 The samples are withdrawn at different time intervals and equal
amount of buffer is replaced each time. The samples are diluted
appropriately and absorbance is determined spectrophotometrically.
Then the amount of drug permeated per centimeter square at each
time interval is calculated.

Factor affecting drug release
 Design of system, patch size, surface area of skin, thickness of
skin and temperature etc. are some variables that may affect the
release of drug. So permeation study involves preparation of skin,
mounting of skin on permeation cell, setting of experimental
conditions like temperature, stirring, sink conditions, withdrawing
samples at different time intervals, sample analysis and
calculation of flux i.e., drug permeated per cm2 per second.

 Preparation of skin for permeation studies: Hairless animal
skin and human cadaver skin are used for permeation studies.
Human cadaver skin may be a logical choice as the skin model
because the final product will be used in humans. But it is not
easily available. So, hairless animal skin is generally favored as
it is easily obtained from animals of specific age group or sex.

 Intact Full thickness skin: Hair on dorsal skin of animal are
removed with animal hair clipper, subcutaneous tissue is
surgically removed and dermis side is wiped with isopropyl
alcohol to remove residual adhering fat. The skin is washed with
distilled water. The skin so prepared is wrapped in aluminum foil
and stored in a freezer at -20C till further use. The skin is
defrosted at room temperature when required.

 Separation of epidermis from full thickness skin: The prepared
full thickness skin is treated with 2M sodium bromide solution in
water for 6 h. The epidermis is separated by using a cotton swab
moistened with distilled water. Then epidermis sheet is cleaned by
washing with distilled water and dried under vacuum. Dried
sheets are stored in desiccators until further use

In vivo Studies
 In vivo evaluations are the true depiction of the drug
performance.
 The variables which cannot be taken into account during in
vitro studies can be fully explored during in vivo studies.
 In vivo evaluation of TDDS can be carried out using:
 Animal models
 Human volunteers

Questions????
 Write a note on transdermal DDS?
 What are the components used in transdermal patches?
 Enlist various tests for evaluation of transdermal patch.
Comments on physico-chemical evaluation of
transdermal patches.
 Write a note on In vitro release studies for transdermal
patches.

Transdermal drug delivery system

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