transdermal drug delivery system
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Transdermal Drug Delivery System
Human Skin
The skin plays an important role in the transdermal drug delivery system. The skin of an average adult
body covers a surface area of approximately 2 sq.m. and receives about one third of the blood circulating
through the body and serves as a permeability barrier against the transdermal absorption of various
chemical and biological agents.
Figure: Various routes of drug absorption.
Different Levels of Drug Effect Seen after Percutaneous Drug Delivery
A Drug applied to the skin may elicit effect at any one of four different levels:
1. An effect on the skin surface
2. An effect within the stratum corneum
3. A more deep seated effect requiring penetration into the living epidermis
4. A systemic effect resulting from sufficient delivery of drug across the layers of skin into the vascular
system
1. Surface effects
An effect on the skin surface may be any one of the following types:
i. Film formation: The film may either be protective (e.g. a zinc oxide cream or a sunscreen) or
occlusive (giving a moisturizing effect)
ii. Antimicrobial effect
iii. A cleansing effect (e.g. effect of soaps or surfactants)
2. Stratum corneum effects
i. Effect of certain sunscreens e.g. p-aminobenzoic acid
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ii. Effect of surface films causing moisturization and consequent softening of skin
iii. Effect of keratolytic agents, such as salicylic acid, causing breakup of stratum corneum cell
aggregates seen in conditions like psoriasis (a disease characterized by thickened scaly plaques)
iv. The stratum corneum may serve as a reservoir or depot for certain drugs that accumulate to a
significant extent in the skin on topical application (e.g. benzocaine, scopolamine and
corticosteroids).
3&4. Epidermal, Dermal, Local & Systemic effects
Penetration of a drug into the viable epidermis and dermis may be difficult to achieve. But once
transepidermal penetration has occurred, the continued diffusion of drug into the dermis may cause
transfer of the drug into the microcirculation of the dermis and then into the general circulation.
Nevertheless, it is possible to formulate a drug delivery system which provides substantial localized drug
delivery without achieving corresponding high systemic concentrations.
Percutaneous Absorption (Sometimes referred as Transdermal absorption)
The absorption of substances from outside the skin to positions beneath the skin including entrance into
the blood stream is referred to as percutaneous absorption.
In Other Words- Percutaneous absorption involves the transfer of drug from the skin surface into the
stratum corneum and its subsequent diffusion through the underlying epidermis & the dermis and into the
microcirculation.
Although the skin has been divided histologically into the stratum corneum, the living epidermis and the
dermis collectively, it can be considered as a laminate of barriers. Passage through this laminate of
barriers can occur by diffusion via: -
1. Transcellular penetration (across the cells)
2. Intercellular penetration (between the cells)
3. Transappendageal penetration (via hair follicles, sweat and sebum glands and pilosebaceous
apparatus)
The major routes of penetration is through the intercellular channels. The role of transappendageal
penetration is very minor because the areas of the skin occupied by these appendages is relatively small.
The skin behaves as a passive barrier to diffusing molecules. The diffusional resistances are encountered
against penetrations of molecules through various regions of skin.
The total diffusional resistance (Rskin) can be given by:
Rskin = Rsc + Re + Rpd
Where R is the diffusional resistance and the subscripts sc, e and pd refers to the stratum corneum,
epidermis and papillary layer of the dermis respectively.
By and large, the greatest resistance to penetration is met in the stratum corneum, i.e. diffusion through
the stratum corneum tends to be rate limiting step.
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Once through the stratum corneum, the molecules may then pass through the deeper epidermal tissues
and into the dermis. When the drug reaches the vascularized dermal layer it is available for absorption
into general circulation.
Factors Affecting Percutaneous Absorption
Among the factors playing a part in the percutaneous absorption of drugs are: the nature of the drug itself,
the nature of the vehicle, the condition of the skin and the presence of moisture.
Although it is difficult to draw general statements applicable to all possible combinations of drug, vehicle
and skin, a summarized account covering majority of research findings can be given as follows:
1. Drug Concentration: Generally the amount of drug percuteneously absorbed per unit of surface area
per time interval increases as the concentration of the drug substance in the vehicle is increased.
2. Surface area of the application site: More drug is absorbed through percutaneous absorption when
the drug substance is applied to a larger surface area.
3. Aqueous solubility and partition coefficient of drug: The drug substance should have a greater
physicochemical attraction to the skin then to the vehicle in order for the drug to leave the vehicle in
favor of the skin.
However some degree of solubility of the drug substance in both lipid and water is thought to be essential
for effective percutaneous absorption. In essence, the aqueous solubility of the drug and the partition
coefficient strongly influences the rate of transport across the absorption site.
(Solutes with molecular weights below 800 to 1000 with adequate solubility in water can permeate the
skin).
4. Vehicle characteristics: 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.
5. Occlusion of the skin: Occluding the skin surface with oleaginous vehicles (e.g. HC base) or occlusive
bandages causes increased percutaneous absorption as a result of increased hydration of the skin (due to
prevention of moisture loss from the skin surface) and increased skin temperature (~2-3) (causing
increased molecular motion).
6. The degree of rubbing or inunctions: In general the degree of rubbing or inunctions of the topical
application will have a bearing on the amount of drug absorbed. The greater the period of inunction, the
greater the absorption.
7. Thickness of the stratum corneum in the application site: The degree of percutaneous absorption
from a skin site with a thin horny layer appears to be greater than one with a thick or callused horny
layer.
Thus the degree of absorption from the palms of the hands and the soles of the feet is comparatively
slower than the body horny layers.
8. The length of the application period: Generally the longer the period of time the medicated
application is permitted to remain in contact with the skin, the greater will be the absorption.
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(However, changes in the hydration of the skin during the application period or the saturation of the skin
with the drug could decrease absorption with increasing time).
9. Number/frequency of application per day: Multiple-application dosing (dosing the same site more
than once a day) rather than single bolus application can increase the absorption and bioavailability.
10. Percutaneous absorption/penetration enhancer: The term “penetration enhancers” is used to
describe materials that have a direct effect on the permeability of the skin.
Among the agents credited with enhancing skin penetration are: surfactants, dimethyl sulfoxide (DMSO),
dimethyl acetamide (DMA), alcohol, acetone, propylene glycol and polyethelene glycol.
[But in view of its effectiveness and safety, water is probably the best ultimate penetration enhancer].
Transdermal Drug Delivery Systems
Transdermal drug delivery systems are designed to support the passage of drug substances from the
surface of the skin, through its various layers, into the systemic circulation. Physically, these systems are
sophisticated patches.
There are two basic types of transdermal dosing systems:
1. Those that allow the skin to control the rate of drug absorption.
2. Those that control the rate of drug delivery to the skin.
The first type is useful for drugs for which a wide range of plasma concentration is effective, but not
toxic.
For these drugs, transdermal dosage forms may be developed of various size and concentrations, with
physician increasing the dose or transdermal application until the desired effect is obtained.
However, for many drugs, it is important to control the predictable rate of drug delivery and percutaneous
absorption.
In these instances, effective transdermal drug delivery systems deliver uniform quantities of drug to the
skin over a period of time.
The amount of drug delivered per unit of time may varied with different types of skin and thus, the drug
delivery system, and not the skin, controls the amount of drug entering the circulation.
Design features and objectives
Included among the designed features and objectives of rate-controlling transdermal drug delivery
systems are the followings:
1. Deliver the drug substances at a controlled rate, to the intact skin of patients, for absorption into the
systemic circulation.
2. The system should possess the proper physico-chemical characteristics to permit the ready release of
the drug substance and facilitate its partition from the delivery system into the stratum corneum.
3. The system should occlude the skin to ensure the one–way flux of the drug substance.
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4. The transdermal system should have a therapeutic advantage over other dosage forms and drug
delivery systems.
5. The system's adhesive, vehicle and active agent should be non–irritating and non–sensitizing to the
skin of the patient.
6. The patch should adhere well to the patient’s skin and its physical size and appearance and placement
on the body should not be deterrent to use.
7. The system should not permit the proliferation of skin bacteria beneath the occlusion.
TYPES OF TRANSDERMAL PATCHES
There are various types of Transdermal Patches:
1. Single layer drug in adhesive
In this type, the adhesive layer contains the drug. The adhesive layer not only serves to adhere the various
layers together but also responsible for releasing the drug to the skin.
The adhesive layer is surrounded by a temporary liner and a backing.
2. Multi-layer drug in adhesive
This type is also similar to the single layer but it contains an immediate drug release layer and other layer
will be a controlled release along with the adhesive layer.
The adhesive layer is responsible for the releasing of drug.
This patch also has a temporary liner-layer and a permanent backing.
3. Vapour patch
In this type of patch, the role of adhesive layer not only serves to adhere the various layers together but
also serves as release vapour.
These are new to the market, commonly used for releasing of essential oils in decongestion.
Various other types of vapor patches are also available in the market which are used to improve the
quality of sleep and reduces the cigarette smoking conditions.
4. Reservoir system
In this system the drug reservoir is embedded between an impervious backing layer and rate controlling
membrane. The drug releases only through the rate controlling membrane, which can be micro porous or
non porous.
In the drug reservoir compartment, the drug can be in the form of a solution, suspension, gel or dispersed
in a solid polymer matrix.
Hypoallergenic adhesive polymer can be applied as outer surface polymeric membrane which is
compatible with drug.
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Figure: Representative designs of transdermal drug delivery systems.
5. Matrix system
i. Drug-in-adhesive system: In this type the drug reservoir is formed by dispersing the drug in an
adhesive polymer and then spreading the medicated adhesive polymer by solvent casting or melting on an
impervious backing layer. On top of the reservoir, unmediated adhesive polymer layers are applied for
protection purpose.
ii. Matrix-dispersion system
In this type the drug is dispersed homogenously in a hydrophilic or lipophilic polymer matrix. This drug
containing polymer disk is fixed on to an occlusive base plate in a compartment fabricated from a drug
impermeable backing layer.
Instead of applying the adhesive on the face of the drug reservoir, it is spread along with the
circumference to form a strip of adhesive rim.
6. Micro-reservoir system
In this type, the drug delivery system is a combination of reservoir and matrix-dispersion system.
The drug reservoir is formed by first suspending the drug in an aqueous solution of water soluble polymer
and then dispersing the solution homogeneously in a lipophilic polymer to form thousands of
unreachable, microscopic spheres of drug reservoirs.
This thermodynamically unstable dispersion is stabilized quickly by immediately cross-linking the
polymer in situ by using cross linking agents.
BASIC COMPONENTS OF TDDS
1. Polymer matrix
Polymer is an integral and foremost important component of transdermal drug delivery systems. Different
classes of polymeric materials have been used to achieve rate controlled drug delivery.
The mechanism of drug release depends upon the physicochemical properties of the drug and polymer
used in the manufacture of the device.
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The following criteria should be satisfied for a polymer to be used in a transdermal system:
Molecular weight, glass transition temperature, chemical functionality or polymer must allow
diffusion and release of the specific drug.
The polymer should permit the incorporation of a large amount of drug.
The polymer should not react, physically or chemically with the drug
The polymer should be easily manufactured and fabricated into the desired product and in
expensive.
The polymer must be stable and must not decompose in the presence of drug and other excipients
used in the formulation, at high humidity conditions, or at body temperature.
Polymers and its degradation products must be non toxic.
2. Drug substance
The selection of drug for transdermal drug delivery depends upon various factors. For developing a
transdermal drug delivery system, the drug has to be chosen with great care. Following are some of the
desirable properties of a drug suitable for transdermal delivery:
i. Physicochemical properties
The drug should have some degree of solubility in both oil and water.
The substance should have melting point less than 200°F.
Substances having a molecular weight of less than 1000 units are suitable.
A saturated aqueous solution of the drug should have a pH value between 5 and 9.
Hydrogen bonding groups should be less than 2.
ii. Biological properties
Drug should be very potent, i.e. it should be effective in few mgs per day (ideally less than 25
mg/day).
The drug should have short biological half life.
The drug should be non irritant and non allergic to human skin.
The drug should be stable when in contact with the skin.
The drug should not stimulate an immune reaction to the skin.
Tolerance to drug must not develop under near zero order release profile of transdermal delivery.
The drug should not get irreversibly bound in the subcutaneous tissue.
The drug should not get extensively metabolized in the skin.
3. Penetration enhancers
These are the compounds, which promote skin permeability and are considered as an integral part of most
transdermal formulations. To achieve and maintain therapeutic concentration of drug in the blood, the
resistance of skin to diffusion of drugs has to be reduced in order to allow drug molecules to cross skin.
These may conveniently be classified under the following main headings:
a. Solvents
These compounds increase penetration possibly by swelling the polar pathway. Examples include
methanol and ethanol; dimethyl sulfoxide, dimethyl acetamide and dimethyl formamide; dimethyl
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pyrrolidone; and miscellaneous solvents like 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.
Examples of commonly used surfactants are:
Anionic surfactants : Dioctyl sulphosuccinate, Sodium lauryl sulphate, Decodecylmethyl sulphoxide etc.
Nonionic surfactants: Pluronic F127, Pluronic F68 etc.
Bile salts: propylene glycol-oleic acid and 1, 4-butane diol-linoleic acid.
c. Miscellaneous chemicals
These include urea, a hydrating and keratolytic agent; dimethyl tolumide; calcium thioglycolate; anti-
cholinergic agents.
4. Drug reservoir components
It must be compatible with the drug and must allow for drug transport at the desired rate.
If an ointment is used, the drug reservoir must possess the desired viscosity attributes to ensure reliable
manufacturing process. It must possess the desired adhesive and cohesive properties to hold the system
together.
Materials used are: mineral oils, polyisobutylene, and colloidal silica, HPC.
Figure: Different layers of TDDS.
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5. Backing laminates
The primary function of the backing laminate is to provide support. They should be able to prevent drug
from leaving the dosage form through top. They must be impermeable to drugs and permeation
enhancers; should have a low moisture vapor transmission rate; must have optimal elasticity, flexibility,
and tensile strength; must be chemically compatible with the drug, enhancer, adhesive and other
excipients; must be relatively inexpensive and allow printing and adhesive lamination.
Type backing membranes are composed of a pigmented layers, an aluminum vapor coated layer, a plastic
film (polyethylene, polyvinyl chloride, polyester) and a heat seal layer.
6. Rate controlling membrane
Rate controlling membranes in transdermal devices govern drug release from the dosage form.
Membranes made from natural polymeric material such as chitosan show great promise for use as rate
controlling membranes.
Recently composite polyhydroxyethyl methacrylate membranes have been evaluated as rate controlling
barriers for transdermal application.
7. Adhesive layer
The fasting of all transdermal devices to the skin using a pressure sensitive adhesive that can be
positioned on the face or in the back of device is necessary.
It should not cause irritation, sensitization or imbalance in the normal skin flora during its contact with
the skin. It should adhere to the skin aggressively.
The three major classes of polymers evaluated for potential medical applications in TDDS include:
Polyisobutylene type pressure sensitive adhesives.
Acrylic type pressure sensitive adhesives.
Silicone type pressure sensitive adhesives.
8. Release liners
The release liner has to be removed before the application of transdermal system, and it prevents the loss
of the drug that has migrated into the adhesive layer during storage. It also helps to prevent
contamination.
It is composed of a base layer, which may be non-occlusive or occlusive, and a release coating layer
made of silicon or Teflon. Other materials include polyesters, foil and metallized laminates.
Technology of Transdermal Drug Delivery System
(Basic manufacturing Designs)
Technically, transdermal drug delivery systems may be categorized into two types:
1. Monolithic systems
2. Membrane controlled systems
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1. Monolithic system: Monolithic systems incorporate a drug matrix layer between backing and frontal
layers.
The drug matrix layer is composed of a polymeric material in which the drug is dispersed. The polymer
matrix controls the rate at which the drug is released for percutaneous absorption.
Nitro-Dur (Key) and Nitrodisc (Searle) are the examples of monolithic systems.
In the preparation of monolithic systems, the drug and the polymer are dissolved or blended together, cast
as the matrix and dried.
The gelled matrix may be produced in sheet or cylindrical form, with individual dosage units cut and
assembled between the backing and frontal layers.
Most transdermal drug delivery systems are designed to contain an excess of drug and thus have drug
releasing capacity beyond the time-frame recommended for replacement.
This ensures continued drug availability and absorption as used patches are replaced on schedule with
fresh ones.
2. Membrane Controlled Transdermal Systems: Membrane-controlled transdermal systems are
designed to contain a drug reservoir, usually in liquid or gel form, a rate controlling membrane and
adhesive or protective backing.
In membrane-controlled systems, a small quantity of drug is frequently placed in the adhesive layer to
initiate prompt drug absorption and therapeutic effects upon placement into the skin.
Transderm – Nitro (Sumit) and Transderm – Scop (CIBA) are the examples of this technology.
Membrane controlled systems have the advantage over monolithic systems in that, as long as the drug
solution in the reservoir remains saturated, the release rate of drug through the controlling membrane
remains constant.
Membrane controlled systems may be prepared by preconstructing the delivery unit, filling the drug
reservoir and sealing or lamination with controlling membrane.
Examples of Transdermal Systems in Use
1. Transdermal Scopolamine Systems
2. Transdermal Nitroglycerine Systems
3. Transdermal Clonidine Systems
4. Transdermal Estradiol Systems
5. Other Transdermal Therapeutic Systems:
i. A Testosterone Transdermal Systems [Testoderm (Alza)]
ii. A Salicylic Acid Transdermal System [Trans-Ver-Sal (Tsumura Medical)]
6. Others TDDSs under study:
i. Isosorbide Nitrate, propranolol and mepindolol and cardiovascular drugs
ii. Levonorgestrel / estradiol for contraception.
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Advantages of TDDS
Among the advantages of TDDSs are the followings:
1. Avoid gastrointestinal drug absorption difficulties caused by gastrointestinal pH, enzymatic activity
and drug interactions with food, drink or other orally administered drugs.
2. Substitute for oral administration of medication when that route is unsuitable, as in instances of
vomiting and / or diarrhea.
3. Avoid the 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 deactivation by
digestive and liver enzymes.
4. Avoid the risks and inconveniences of parenteral therapy and the variable absorption and metabolism
associated with oral therapy.
5. Provide the capacity for multi–day therapy with a single application therapy improving patient
compliance over use of other dosage forms requiring more frequent dose administration.
6. Extend the activity of drugs having short half-lives through the reservoir of the drug present in the
therapeutic delivery system and its controlled release characteristics.
7. Provide capacity to terminate the effect rapidly (if clinically desired) by removal of drug application
from the surface of the skin.
8. Provide ease of rapid identification of the medication in emergencies (e.g. nonresponsive, unconscious,
or comatose patients).
Disadvantages of TDDS
Among the disadvantages of TDDSs are the followings:
1. The transdermal route of administration is unsuitable for drugs that irritate or sensitize the skin.
2. Only relatively potent drugs are suitable candidates for transdermal delivery due to natural limits of
drug entry imposed by skin’s impermeability.
3. Technical difficulties are associated with the adhesion of systems to different skin types and under
various environmental conditions.
4. The development of rate-controlling drug delivery features which are not economically feasible and
therapeutically effective for many drug substances.
General considerations in the use of TDDS
Some general points applicable to the use of transdermal patches include the following:
1. The site selected for the application should be clear, dry and hairless (but not shaved). [Nitroglycerin
patches are generally applied to the chest, estradiol to the buttocks or the abdomen, scopolamine behind
the ear and nicotine to the upper trunk or upper outer arm.]
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Because of the possible occurrence of skin irritation, the site of application for replacement patches is
rotated. Skin sites generally are not reused for a week.
2. 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.)
3. The patch should be removed from its protective package, being careful not to tear or cut it. The
patch's protective backing should be removed to expose the adhesive layer, and it should be applied
firmly with the palm or heel of the hand until securely in place (about 10 seconds).
4. The patches should be worn for the period of time stated in the product's instructions. Following that
period the patch should be removed and a fresh patch applied as directed. The used patch should be
folded in half with the adhesive layer together so that it cannot be reused.
5. Patches generally may be left on when showering, bathing or swimming. Should a patch prematurely
dislodge, an attempt may be made to reapply it, or it may be replaced with a fresh patch.
6. The patient should be instructed to clean 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.
7. As with all medications, if the patient exhibits sensitivity or intolerance to the drug, or if undue skin
irritation results, the patient should seek re-evaluation.
Monitor
Abdul Gaffar(01717604661) [email protected]