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Friday, May 15, 2009



Panicker Sharathchandran Sasidharan, Vimal Mathew

National College of Pharmacy, Manassery, Calicut


Continuous intravenous infusion is recognized as a superior mode of drug administration not only to bypass hepatic "first-pass" metabolism, but also to maintain a constant and prolonged drug level in the body. A closely monitored intravenous infusion can provide the advantages of both direct entry of drug into the systemic circulation and control of circulating drug levels. However, such mode of drug administration entails certain risks and, therefore, necessitates hospitalization of the patients and close medical supervision of administration.

Recently, it is becoming evident that the benefits of intravenous drug infusion can be closely duplicated, without its hazards, by using the skin as the port of drug administration to provide continuous transdermal drug infusion into the systemic circulation [1].

To provide continuous drug infusion through an intact skin, several transdermal therapeutic systems have been developed for topical application onto the intact skin surface to control the delivery of drug and its subsequent permeation through the skin tissue. It is exemplified by the development and marketing of scopolamine-releasing transdermal therapeutic system for 72-hr prophylaxis or treatment of motion-induced nausea [2], of nitroglycerin and isosorbide dinitrate-releasing trans-dermal therapeutic systems for once-a-day medication of angina pectoris [3.4], and of clonidine-releasing transdermal therapeutic system for weekly treatment of hypertension [4]. The intensity of interests in the potential biomedical applications of transdermal controlled drug administration is demonstrated in the increasing research activities in a number of health care institutions in the development of various types of transdermal therapeutic systems for long term continuous infusion of therapeutic agents, including antihypertensive, anti-anginal, anti-histamine, anti-inflammatory, analgesic, anti-arthritic, steroidal, and contraceptive drugs.

This chapter intends to review fundamentals of skin permeation, approaches for transdermal controlled drug administration, in vitro and in vivo kinetic evaluations of transdermal therapeutic systems and their correlations, as well as formulation design and optimization.

Skin and drug permeation

For understanding the concept of transdermal drug delivery systems, it is important to review the structural and biochemical features of human skin and those characteristics which contribute to the barrier function and the rate of drug access into the body via skin.

The Skin

The skin is one the most extensive organs of the human body covering an area of about 2m2 in an average human adult. The skin separates the underlying blood circulation network from the outside environment, serves as a barrier against physical, chemical and microbial attacks, acts as a thermostat in maintaining body temperature, protects against harmful ultraviolet rays of the sun and plays a role in the regulation of blood pressure.

Anatomically, the skin has many histologic layers but in general, it is described in terms of three major tissue layers: the epidermis, the dermis and the hypodermis.

The epidermis results from an active epithelial basal cell population and is approximately 150 micrometers thick. It is the outermost layer of the skin and the process of differentiation results in migration of cells from the basal layer towards the skin surface. The end result of this process is the formation of a thin, stratified and extremely resilient layer at the skin surface. Below this layer are the other layers of the epidermis - the stratum lucidum, stratum granulosum, stratum spinosum and stratum germinativum. Together, these other layers constitute the viable epidermis.

The stratum corneum or the horny layer is the rate-limiting barrier that restricts the inward and outward movement of chemical substances. The interior of the cells is crisscrossed with densely packed bundles of keratin fibres. Due to this, the dry composition of the horny layer is 75-85% protein, most of which is the intracellular keratin and a part being associated with a network of cell membranes. The bulk of the remainder of the substance of the stratum corneum is a complicated mixture of lipids which lies between regions, the mass of intracellular protein and the intercellular lipoidal medium.

The epidermis rests on the much thicker dermis. The dermis essentially consists of about 80% of protein in a matrix of muco-polysaccharide "ground substance". A rich bed of capillaries is encountered 20 mm or so into the dermal field. Also contained within the dermis are lymphatics nerves and the epidermal appendages such as hair follicles, sebaceous glands and sweat glands. Excepting the soles of the feet, the palms of the hand, the red portion of the lips and associated with one or more sebaceous glands which are outgrowths of epithelial cells. The sweat gland are divided into the eccrine and apocrine types and are widely distributed over the surfaces of the body. The sweat glands serve to control body heat by secretion of a dilute salt solution.

Percutaneous Absorption

Percutaneous absorption involves passive diffusion of substances through the skin. The mechanism of permeation can involve passage through the epidermis itself or diffusion through shunts, particularly those offered by the relatively widely distributed hair follicles and eccrine glands.

Transepidermal absorption

The trans-epidermal pathway is principally responsible for diffusion across the skin. The main resistance encountered along this pathway arises in the stratum corneum. Permeation by the trans-epidermal route first involves partitioning into the stratum corneum. Diffusion then takes place across this tissue. The current popular belief is that most substances diffuse across the stratum corneum via the intercellular lipoidal route. However, there appears to be another microscopic path through the stratum corneum for extremely polar compounds and ions. When a permeating drug exits at the stratum corneum, it enters the wet cell mass of the epidermis and since the epidermis has no direct blood supply, the drug is forced to diffuse across it to reach the vasculature immediately beneath. It is a permeable field that functions as a viscid watery regime to most penetrants. It appears that only ions and polar non-electrolytes found at the hydrophilic extreme and lipophilic non-electrolytes at the hydrophobic extreme have any real difficulty in passing through the viable field. The epidermal cell membranes are tightly joined and there is little to no intercellular space for ions and polar non-electrolyte molecules to diffusionally squeeze through.

Passage through the dermal region represents a final hurdle to systemic entry. Permeation through the dermis is through the interlocking channels of the ground substance. Since the viable epidermis and dermis lack major physicochemical distinction, they are generally considered as a single field of diffusion, except when penetrants of extreme polarity are involved, as the epidermis offers measurable resistance to such species.

Transfollicular (shunt pathway) absorption

The skin's appendages offer only secondary avenues for permeations. Sebaceous and eccrine glands are the only appendages which are seriously considered as shunts bypassing the stratum corneum since these are distributed over the entire body. Though eccrine glands are numerous, their orifices are tiny and add up to a miniscule fraction of the body's surface. Moreover, they are either evacuated or so profusely active that molecules cannot diffuse inwardly against the gland's output. For these reasons, they are not considered as a serious route for percutaneous absorption. However, the follicular route remains an important avenue for percutaneous absorption since the opening of the follicular pore, where the hair shaft exits the skin, is relatively large and sebum aids in diffusion of penetrants. Partitioning into sebum, followed by diffusion through the sebum to the depths of the epidermis, is the envisioned mechanism of permeation by this route. Vasculature subserving the hair follicle located in the dermis is the likely point of systemic entry.

Clearance by local circulation

The earliest possible point of entry of drugs and chemicals into the systemic circulation is within the papillary plexus in the upper dermis. The process of percutaneous absorption is general, regarded as ending at this point. However, some molecules bypass the circulation and diffuse deeper in the dermis.


Trans-dermal 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.

The rate of permeation across the skin is given by


where Cd and Cr are the concentrations of skin penetrant in the donor compartment and in the receptor compartment. Ps is the overall permeability coefficient of the skin tissues to the penetrant. This permeability coefficient is given by the relationship:


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, ie., the drug concentration at the surface of the stratum corneum (Cd) is consistently and substantially greater than the drug concentration in the body (Cr). Then the equation (1) becomes:


and the rate of skin permeation (dQ/dt) 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) that is either constant or greater than the rate of skin uptake (Ra). This is shown in Fig. 5.2

Since Rr is greater than 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). Therefore, a maximum rate of skin permeation is obtained and is given by the equation:

(dQ/dt)m = Ps Cs

from the above equation, it can be seen that the maximum rate of skin permeation depends on the skin permeability coefficient (Ps) and its equilibrium solubility int eh stratum corneum (Cs).


Figure representing transdermal patch

  1. Release of medicament from the vehicle
  2. Penetration through the skin barriers;
  3. Activation of the pharmacological response.

Effective therapy optimizes these steps as they are affected by three components, the drug, the vehicle and the skin.

Figure which represents the movement of drug molecules arising from, for example, a trans-dermal drug delivery system with a rate-controlling membrane, illustrates the complexity of percutaneous absorption. Any drug particles must first dissolve so that molecules may diffuse towards the membrane within the patch. The penetrant partitions into the membrane, diffuse across the polymer and partitions into the skin adhesive. The molecules diffuse towards the vehicle/stratum corneum interface. They then partition into the stratum corneum and diffuse through it. Some drug may bind at a depot site; the remainder permeates further, meets a second interface, and partitions into the viable epidermis. For a lipophilic species this partition coefficient may be unfavourable, ie., less than 1. Within the epidermis, enzymes may metabolize the drug or it may interact at a receptor site.

After passing into the dermis, additional depot regions and metabolic sites may intervene as the drug moves to a capillary, partitions into its wall and out into the blood for systemic removal. A fraction of the diffusant may partition into the subcutaneous fat to form a further depot. A portion of the drug can reach deep muscle layers, as illustrated by, for example, the efficacy of non-steroidal anti-inflammatory drugs.

However, there are further complications. The following factors may be important: the non-homogeneity of the tissues; the presence of lymphatics; interstitial fluid; hair follicles and sweat glands; cell division; cell transport to and through the stratum corneum; and cell surface loss. The disease, the healing process, the drug and vehicle components may progressively modify the skin barrier. As vehicle ingredients diffuse into the skin, cellular debris, sweat, sebum and surface contaminants pass into the dermis, changing its physicochemical characteristics. Emulsions may invert or crack when rubbed in, and volatile solvents may evaporate.


The components of transdermal devices include:

  1. Polymer matrix or matrices
  2. The drug permeation enhancers
  3. Other excipients


The polymer controls the release of the drug from the device. The following criteria should be satisfied for a polymer to be used in a transdermal system (Kydoineus & Berner, 1987):

  1. Molecular weight, glass transition temperature and chemical functionality of the polymer should be such that the specific drug diffuses properly and gets released through it.
  2. The polymer should be stable, non-reactive with the drug, easily manufactured and fabricated into the desired product; and inexpensive.
  3. The polymer and its degradation products must be non-toxic or non-antagonistic to the host.
  4. The mechanical properties of the polymer should not deteriorate excessively when large amounts of active agent are incorporated into it.

Possible useful polymer for trans-dermal devices are:

Natural polymers

Cellulose derivatives, Zein, Gelatin, Shellac, Waxes, Proteins, Gums and their derivatives, Natural rubber, starch etc.

Synthetic elastomers

Polybutadiene, Hydrin rubber, Polysiloxane, Silicone rubber, Nitrile, Acrylonitrile, Butyl rubber, Styrenebutadiene rubber, Neoprene etc.

Synthetic polymers

Polyvinyl alcohol, Poly vinyl chloride, Polyethylene, Polypropylene, Polyacrylate, Polyamide, Polyurea, Polyvinylpyrrolidone, Polymethylmethacrylate, etc.


For successfully developing a trans-dermal drug delivery system, the drug should be chosen with great care. The following are some of the desirable properties of a drug for trans-dermal 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 portioning characteristics are not conducive to successful drug delivery via the skin.
  3. The drug should have a low melting point.

Biological properties

  1. The drug should be potent with a daily dose of the order of a few mg/day.
  2. The half life (t1/2) of the drug should be short.
  3. The drug must not induce a cutaneous irritant or allergic response.
  4. Drugs which degrade in the GI tract or are inactivated by hepatic first pass effect are suitable candidates for trans-dermal delivery.
  5. Tolerance to the drug must not develop under the near zero-order release profile of trans-dermal delivery.
  6. Drugs which have to be administered for a long period of time or which cause adverse effects to non-target tissues can also be formulated for trans-dermal delivery.


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

The flux, J, of drugs across the skin can be written as:

where D is the diffusion coefficient and is a function of the size, shape and flexibility of the diffusing molecule as well as the membrane resistance; C is the concentration of the diffusing species; x is the spatial coordinate.

Enhancement of flux across membranes reduces to considerations of:

  • Thermodynamics (lattice energies, distribution coefficients)
  • Molecular size and shape
  • Reducing the energy required to make a molecular hole in the membrane

These may conveniently be classified under the following main headings:


These compounds increase penetration possibly by swelling the polar pathway. 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-methyil, 2-pyrrolidone; laurocapram (Azone) miscellaneous solvents – propylene glycol, glycerol, silicone fluids, isopropyl palmitate.


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. These compounds are, however, skin irritants, therefore, a balance between penetration enhancement and irritation has to be considered. Anionic surfactants can penetrate and interact strongly with the skin. Once these surfactants have penetrated the skin, they can induce large alterations. Cationic surfactants are reportedly more irritant than the anionic surfactants, the nonionics have long been recognized as those with the least potential for irritation and have been widely studied. 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

These systems apparently open up the heterogeneous multi-laminate pathway as well as the continuous pathways. Examples include: propylene glycol-oleic acid and 1, 4-butane diol-linoleic acid

Miscellaneous chemicals

These include urea, a hydrating and keratolytic agent; N, N-dimethyl-m-tolumide; calcium thioglycolate; anti-cholinergic agents.



The fastening of all trans-dermal devices to the skin has so far been done by using a pressure sensitive adhesive. The pressure sensitive adhesive 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

  1. Should not irritate or sensitize the skin or cause an imbalance in the normal skin flora during its contact time with the skin.
  2. Should adhere to the skin aggressively during the dosing interval without its position being distrurbed by activities such as bathing, exercise etc.
  3. Should be easily removed.
  4. Should not leave an unwashable residue on the skin
  5. Should have excellent (intimate) contact with the skin at macroscopic and microscopic level.

The face adhesive system should also fulfill the following criteria.

  1. Physical and chemical compatibility with the drug, excipients and enhancers of the device of which it is a part.
  2. Permeation of drug should not be affected.
  3. The delivery of simple or blended permeation enhancers should not be affected.

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, adhesive foam pad with occlusive base plate etc.


Four different approaches have been utilized to obtain trans-dermal drug delivery systems:


Fig. 5.3 Membrane-moderated trans-dermal drug delivery system

In this type of system, the drug reservoir is totally encapsulated in a shallow compartment moulded from a drug-impermeable metallic plastic laminate and a rate controlling polymeric membrane which may be micro-porous or non-porous e.g., ethylene vinyl acetate (EVA) copolymer, with a defined drug permeability property. A cross-sectional view of this system is shown in figure. The drug molecules are permitted to release only through the rate-controlling membrane. In the drug reservoir compartment, the drug solids are either dispersed in a solid polymer matrix or suspended in an unleachable, viscous liquid medium such as silicone fluid to form a paste like suspension. A thin layer of drug compatible, hypoallergenic adhesive polymer e.g. silicone or polyacrylate adhesive may be applied to the external surface of the rate controlling membrane to achieve an intimate contact of the trans-dermal system and the skin surface the rate of drug release from this type of trans-dermal drug delivery system can be tailored by varying the polymer composition, permeability coefficient and thickness of the rate limiting membrane and adhesive.

The constant release rate of the drug is the major advantage of membrane permeation controlled trans-dermal system. However, a rare risk also exist when an accidental breakage of the rate controlling membrane can result in dose dumping or a rapid release of the entire drug content. Examples of this system are:

  • Nitroglycerin-releasing trans-dermal system for once a day medicatin in angina pectoris.
  • Scopolamine-releasing trans-dermal system prophylaxis of motion sickness
  • Estradiol-releasing trans-dermal system for treatment of menopausal syndrome for 3-4 days

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

where CR is the drug concentration in the reservoir compartment and Pa and Pm are the permeability coefficients of the adhesive layer and the rate controlling membrane, respectively. For a micro-porous membrane, Pm is the sum of permeability coefficients for simulations penetration across the pores and the polymeric material Pm and Pa respectively, are defined as follows:

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 the adhesive respectively; Dm and Da are the diffusion coefficients in the rate controlling membrane and adhesive layer respectively; and hm and ha are the membrane, the porosity and tortuosity of the membrane should be taken into the calculation of the Dm and hm values. Substituting equations for Pm and Pa

which defines the intrinsic rate of drug release from a membrane moderated drug delivery system.


This is a simplified form of the membrane permeation controlled system. As represented in figure the drug reservoir is formulated by directly dispersing the drug in an adhesive polymer eg. Poly (isobutylene) or poly (acrylate) adhesive and then spreading the medicated adhesive, by solvent casting or hot melt, on to the flat sheet of drug impermeable metallic plastic backing to form a thin drug reservoir layer.

On top of the drug reservoir layer, thin layers of non-medicated, rate controlling adhesive polymer of a specific permeability and constant thickness are applied to produce an adhesive diffusion-controlled delivery system. An example of this type of system is isosorbide dinitrate releasing trans-dermal therapeutic system for once a day medication of angina pectoris. This adhesive diffusion controlled drug delivery system is also applicable to the trans-dermal controlled administration of verapamil.

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

where Ka/r is the partition coefficient for the interfacial portioning of the drug from the reservoir layer to adhesive layer.


In this approach, the drug reservoir is prepared by homogeneously dispersing drug particles in a hydrophilic or lipophilic polymer matrix. The resultant medicated polymer is then moulded into a medicated disc with a defined surface area and controlled thickness. The dispersion of drug particles in the polymer matrix can be accomplished by either homogeneously mixing the finely ground drug particles with a liquid polymer or a highly viscous base polymer followed by cross linking of the polymer chains or homogeneously blending drug solids with a rubbery polymer at an elevated temperature. The drug reservoir can also be formed by dissolving the drug and polymer in a common solvent followed by solvent evaporation in a mould at an elevated temperature and/or under vacuum. This drug reservoir containing polymer disc is then pasted on to an occlusive polymer is then spread along the circumference to form a strip of adhesive rim around the medicated disc.

This type of trans-dermal system is exemplified by the nitroglycerin releasing trans-dermal therapeutic systems. These are designed to be applied to the intact skin to provide a continuous trans-dermal infusion of nitroglycerin at a daily dose of 0.5 mg/cm2 for therapy of angina pectoris. It is a modified version of NitroDur in which the drug is dispersed in an acrylic based polymer adhesive with a resinous cross linking agent which results in a much thinner and more elegant patch. Patent disclosures have also been filed for applying this drug delivery system for trans-dermal controlled administration of estradiol discetyate and verapamil.

The rate of drug release from this type of system is defined as:

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.


This can be considered a combination of the reservoir and matrix diffusion type drug delivery systems. Here the drug reservoir is formed by first suspending the drug solids in an aqueous solution of a water soluble liquid polymer and then dispersing the drug suspension homogeneously in a lipophilic polymer viz. silicone elastomers by high energy dispersion technique to form several discrete, unleachable microscopic spheres of drug reservoirs. The quick stabilization of this thermodynamically unstable dispersion is accomplished by immediately cross linking the polymer chains in situ which produces a medicated polymer disc with a constant surface area and a fixed thickness. Depending upon the physiochemical property of the drug and the desired rate of drug release, the device can be further coated with a layer of biocompatible polymer to modify the mechanism and rate of drug release. A trans-dermal therapeutic system is produced by positioning the medicated disc at the centre and surrounding it with an adhesive rim.

The rate of release of drugs from the micro-reservoir system is defined by

where m = a/b, a is the ratio of the drug concentration in the bulk of the elution medium over drug solubility in the same medium and b is the ratio of drug concentration at the outer edge of the polymer coating over the drug solubility into the same polymer composition; n is the ratio of drug concentration at the inner edge of the interfacial barrier over drug solubility in the polymer matrix; Dl and Dp and Dd are respectively the drug diffusivities in the liquid layer surrounding the drug particles, polymer coating membrane surrounding the polymer matrix and the hydrodynamic diffusion layer surrounding the polymer coating with respective thickness of h1, hp and hd; Kl Km and Kp are the partition coefficients for the interfacial partitioning of the drug from the liquid compartment to the polymer matrix, from the polymer matrix to the polymer coating membrane and from the polymer coating membrane to the elution solution (or skin) respectively. Sl and Sp are the solubilities of the drug in the liquid compartment and in the polymer matrix respectively.


These systems are poroplastic membrane and a hydrophilic polymeric reservoir. The poroplastic membrane is an open cell ultra-microporous form of cellulose triacetate. It hold saturated drug solution (water or mineral oil) by capillary action, it can also be described as a "molecular sponge". However, the pores are perhaps a million times smaller than those of an ordinary sponge. The molecular weight cut off can then be used to estimate a characteristics pore diameter. The pores have reasonable broad size distribution drug delivery through poroplastic membrane is its diffusive permeability which can be varied over broad range.

A new variation on existing polymeric trans-dermal delivery systems employs hydrophilic gel matrix membrane. The matrix is an "open cell molecular sponge", is a plasticizer which contains a drug in a soluble and/or suspended state in a micro-space suspended by the polymeric meshwork of linkages. It contains one or a mixture of hydrogen bonding liquids such as water, glycerine, propylene glycol, polyethylene glycol etc. comprising from 40-70% patch weight. Gelation agents such as Karaya alginxanthan, guar, locust bean gum and/or synthetic hydrophilic polymers poly-acrylamide polyvinyl sulphonates, polyvinyl alcohol, poly-acrylic acid, polyvinyl pyrolidone and others are also used.



These systems can be multi-laminate products e.g. Trans-derm Scop and Catapress - TTS or "Form fill seal" products e.g. Trans-derm Nitro and Estraderm. Figure shows the manufacturing process flow chart for multi-laminate products.

These products consist of three substrates held together by two layers of drug-containing adhesives. First, the drug is processed into the physical/chemical form required for incorporation into the product. Then, the drug, adhesive components and excipients are mixed with a solvent to achieve uniform solution or dispersion. This step has to be carefully controlled since it determines product composition. These adhesive compositions are deposited as thin films on moving substrates which are subsequently dried to remove solvent. The next step consists of lamination of the dried adhesive film and other layers to form the five layer product consisting of release liner, contact adhesive, control membrane, drug reservoir and backing substrate. The laminate is then printed and die cut into the final dosage form. The film coating and laminating steps are the most critical since precise coating thickness and a wrinkle free laminate require accurate control of process variables.

The products are then packed in individual foil pouches. After inspection the products are automatically inserted into a continuously moving web of pouch stock which is then sealed around the dosage form. Then individual pouches are cut from the web and shingled on a conveyor. Pouches, along with patient and physician inserts, are packed into cartons or blisters and sorted for shipment. A laminate of release liner, contact adhesive and control membrane is prepared and fed into packaging type equipment where discrete portions of drug gel are deposited onto the web, covered with the backing and sealed using heat and pressure. Individual systems are die-punched form the web, packed into foil pouches and then into cartons for shipment. Both these processes are highly automated, continuous processes with a large batch size, of the order of the one million units.


(i) Preparation of individual matrix solutions

Each raw material (polymer, tackifiers, softening agents etc) is dissolved in an organic solvent to obtain a standard or stock solution for each raw material. Then the solid content and other quality parameters are determined. The matrix solution is then prepared form the stock solution by mixing it with ingredients specified by the formulation. On the top of the drug reservoir layer, layers of non-medicated, rate-controlling adhesive polymer of constant thickness are applied to produce an adhesive diffusion controlled drug delivery system. Examples of this type of trans-dermal drug delivery system are the nitroglycerin releasing trans-dermal therapeutic systems such as the Deponit system (Pharma Schwartz).


In these systems, the drug reservoir is formed by homogeneously dispersing the drugs in a hydrophilic or lipophilic polymer matrix, and the medicated polymer then is molded into a medicated disc with a defined surface area and controlled thickness. The disc then is glued onto an occlusive base-plate in a compartment fabricated from a drug impermeable backing. The adhesive polymer is spread along the circumference to form a strip of adhesive rim around the medicated disc. An example of this type of trans-dermal drug delivery system is the nitroglycerin releasing trans-dermal therapeutic system such as the NitroDur system.


In these systems, the drug reservoir is formed by first suspending the drug particles in an aqueous solution of water soluble polymer and then dispersing it homogeneously in a lipophilic polymer by high shear mechanical force to form a large number of unleachable, microscopic spheres of drug reservoirs. This thermodynamically unstable dispersion is stabilized quickly by immediately cross linking the polymer in situ, which produces a medicated polymer disc with a constant surface area and a fixed thickness. A trans-dermal therapeutic system is produced, in which the medicated disc is positioned at the center and surrounded by an adhesive rim.


Figure of nitro-dur

Therapeutic Agent





Habitrol (Novartis Consumer)

Multi-layered round patch:

(1). an aluminized backing film; (2). A pressure-sensitive acrylate adhesive; (3). Methacryclic acid copolymer solution of nicotine dispersed in a pad of nonwoven viscose and cotton; (4) an acrylate adhesive layer; and (5) a protective aluminized release liner that overlays the adhesive layer and is removed prior to use

Transdermal therapeutic systems providing continuous release and systemic delivery of nicotine as an aid in smoking cessation programs. The patches listed vary somewhat in nicotine content and dosing schedules.


Deponit (Schwarz Pharma)

A three-layer system: (1) covering foil; (2). Nitroglycerin matrix with polysobutylene adhesive, plasticizer and release membrane; and (3). Protective foil removed before use.

TDDSs designed to provide the controlled release of nitroglycerin for treatment of angina. Daily application to chest, upper arm or shoulder.


Trnsderm Scop (Novartis Consumer)

Four-layered patch: (1). Backing layer of aluminized polyster film; (2). Drug reservoir of scopolamine, minerl oil, and polyisobutylene; (3). A microporous polypropylene membrane for rate delivery of scopolamine; and (4). Adhesive of polysobutylene, mineral oil, and scopolamine

TDDS for continuous release of scopolamine over a 3-day period as required for the prevention of nausea and vomiting associated with motion sickness. The patch is placed behind the ear. When repeated administration is desired, the first patch is removed and the second patch placed behind the other ear. Also FDA-approved for prevention of nausea associated with certain anesthetics and analgesics used in surgery.


Testoderm (Alza)

Three-layer patch: Backing layer of poly7ethylene terephthalate

The patch is placed on the scrotum in the treatment of testosterone deficiency.



Ketotifen fumarate is effective in low doses in the treatment of bronchial asthma particularly of allergic origin. However, it is substantially metabolized in the liver when administered orally. Hence Trans-dermal patches of combination of Ethylcellulose/Poly vinyl pyrrolidone and Eudragit RS 100/RL 100 were prepared and their drug release kinetics and skin permeation profiles were evaluated. However, the skin permeation profiles were found to be low and sub-therapeutic. Hence three hydrophobic biocompatible substances, viz. Isopropyl myristate, Isopropyl palmitate and linoleic acid and also combination of Isopropyl myristate and linoleic acid were used as permeation enhancers in the film. It was found that Isopropyl myristate and Linoleic acid combination and Isopropyl myristate alone produced promising results compared to Isopropyl palmitate and Linoleic acid.


Ketotifen fumarate (KTF) belongs to tricyclic compound of benzocyclohepatathiophene class is a nonspecific, oral mast cell stabiliser. The prominent biochemical, pharmacological activities are H1 antagonism, phosphodiesterase inhibition and inhibition of calcium flux in smooth muscle preparation. This is useful in allergic asthma and rhinitis. The drug have value in prophylaxis of atopic asthma. The incidence of asthma is 2 to 3 times higher in children than that of an adult.4 Majority of the drug regimen in the treatment of asthma belongs to oral or inhalant class from which a better patient compliance in case of asthma therapeutics management may not be possible. KTF is having 50% oral bio-availability due to hepatic first pass effect in the liver and is metabolised to inactive nor-ketotifen and only 1% of the intact drug is excreted through the kidney.

The low dose therapeutic and substantial biotransformation of KTF makes it an ideal candidate for TDS.Further over a prolonged period sustained blood level of the drug is required for control of allergic asthma and other allergic syndromes. However KTF is a weak base of pka 6.7, so that it exists in a cationic form at skin pH (4.2 5.6) and in this condition absorption through the skin is expected to be sub therapeutic. Therefore KTF requires permeation enhancers to, pass through the skin. The present study was undertaken to' evaluate the effect of three hydrophobic enhancers viz., Isopropyl mysistate (IPM), Isopropylpalmitate (IPP) and linoleic acid (LNA) using KTF with combined

Ethylcellulose (EC) and Polyvinylpyrrolidone (PVP) as well as Eudragit RS 100 and RL 100 matrix type of films. The enhancers whose solubility parameter is nearer to the matrix systems were choosen since such a combination is expected to produce higher penetratin effect.



Eudragits RS 100 and RL 100 (Rohm Pharma, Germany), Polyvinyl pyrrolidone (Loba Chemie, Bombay, M. Wt. 40,000), Polyethylene glycol 400 (Ranbaxy Laboratories), Ethyl Cellulose (BDH, England, viscosity 14 CPS), Ketotifen fumarate (Courtesty, Torrent Laboratories, Ahmedabad), Isopropyl Myristate (Aldrich, USA), Isopropyl Palmitate (Aldrich, USA), Linoleic Acid (Sigma, USA), Diethylene glycol (E. Merck, Germany), Ethylene glycol monostearate (E. Merck, Germany) and Dibutyl pthalate (E.Merck, Germany).

Preparation of Monolithic Matrix Film :

The films were fabricated by casting method as reported earlier6'7 from this laboratory using different combination of polymers. For Eudragit films prepared with RS 100 and RL 100 in the proportions of 3.1 ratio on molecular weight basis was choosen for incorporation of enhancers because those were found to give best release profile. In addition it contains 5% w/w Diethylene glycol (DEG). In case of EC and PVP 4:1 molecular weight ratio was choosen for incorporation of 10% w/w enhancers in each along with 2% w/w Ethylene glycol monostearate (EGM) and 5% w/w DEG for the reason as above. All films contain Dibutylpthalate (DBP) 10% w/w. Drug concentration varied from 4.10 to 4.33 mg. per square centimeter of the film. The prepared and dried films were cut into required dimensions by a die cutter. The film thickness varied from 0.7 to 0.9 mm. The other physicochemical parameters like Moisture vapour transmission, Moisture absorption capacity and Tensile strength were measured and found to be within limit for good TDS films.

Table 1


Enchancers 10% W/W

Drug Concentration (mg/cm2 )

Release flux (mg/cm2/hr)

Permeation flux (mg/cm2/hr)

Lag time (hr)

Diffusion coefficient (cm/sec)

RS 100


RL 100


Plain Film






























Plain film





























In vitro Drug Release Study :

Modified Keshary Chien diffusion cell was used to evaluate the in vitro release of KTF from the transdermal films. The receptor compartment was filled with a solution of 20% vv/v PEG 400 in normal saline which was stirred magnetically and maintained at a constant temperature of 37° ~+ 1°C. Aliquots withdrawn over 12 hours period -and' estimated for the drug content at 301 nm (Hitachi Spectrophotometer, mode U-2001).

Skin Permeation Study:

Freshly exised abdominal skin of 6 to 8 weeks old albino mice were used after pre-treatment as described elsewhere. The skin was fixed onto modified Keshany—Chien diffusion cell'. The elution medium was 20%-w/v PEG-400-saline solution kept at 37° ± 1°C, being stirred magnetically at 500 rpm. Trans-dermal films of 5.76 cm area were placed in intimate contact with stratum corneum side of the skin. Aliquots from the receiving solution were withdrawn periodically upto 30 hours and estimated at 301 nm.


In vitro diffusion kinetics of drug from the films were best described by Higuchi square root equation, which resulted in a linear plot as depicted in Figure 1 and 2, both from EC-PVP and RS 100-RL 100 films. Table 1 shows the release and permeation data which on statistical analysis relates to a high correlation coefficient of 0.9956. Amongst the different skin permeation enhancers used, viz, IMP, IPP and LNA singly and in combination with LNA exhibited higher release rate compared to the control films without enhancers. About 33% of KTF was released from RS 100

RL 100 and 30% from EC:PVP films both containing enhancers as above over a period of 12 hours. The ECPVP films showed initial higher release compared to RS 100: RL 100 films which may be due to initial hydration and swelling of the film where PVP acts as an anti-nucleating agent which retards the crystallisation of the drug and improves the solubility of the drug in the matrix.

Skin Permeation:

Six matrix formulation were investigated for the drug release permeation profile using hair free mouse skin. The permeation of KTF through intact mice skin follow apparent first order kinetics. All formulation showed initial lag time which varied from 2.5 to 3.5 hours (Table 1) then followed by steady state diffusion which may be described by Fick's law under the sink condition. The permeation rate of KTF is greater for RS:RL system. This indicates that the films and skin controls the permeation of KTF. The change of release rate is reflected in a corresponding change of permeation rate 'through skin. It shows that the rate controlling factor is the TDS film itself.

Decreasing rank order of the drug release was observed in both RS:RL and EC:PVP system with enhancer in the manner IMP/LNA mixture>IPM>LNA>IPP. The permeation from RS:RL system with IPM/LNA mixture, as shown in Figures 3, is about 21% more than the plain RS:RL system in 30 hours. Where as in case of EC:PVP the same is 15%. The enhanced release in RS:RL system with IPM/LNA mixture may be due to the formation of a three phase continuous network within the polymer matrix. The diffusivity data are shown in Table 1, which depicts that the films containing IPM and LNA mixture was having highest diffusion coefficient. Moreover, the RS:RL film with IPM and LNA appears to have better diffusivity when compared with EC:PVP film. These data support the principle that for the higher drug release the formulation should possess relatively higher diffusion coefficient value.


Taking into account the advantages of TDDS, it can be considered a perfect alternative for drugs whose enteral and parenteral dosages forms having drawbacks in performance and also in patient compliance. After rectifying the presently excisting short-comings TDDS can surely introduce new dimentions in the field pf drug delivery


  1. Controled and novel drug delivery –N.K.Jain,(Third edition) Pg no:101-127

  1. Pharmaceutics-The science of dosage form and design (Second edition) Edited by M.E.Aulton

Publication –Churchill Livigstone

  1. Pharmaceutical dosage forms and drug delivery systems –Hwards C. Ansel,Loyd. V. Allen,Jr, Nicholas G. Popovich

  1. Barry, B.W. (1983) Dermatological formulation: Percutaneous Absorption. Marcel Decker, New York.

  1. Bronaugh, R.L and Maibach, H.I. (eds) (1989) Percutaneous absorption, Edition-. 3 Marcel Decker, , New York

  1. Chien .Y.W. (1982) Novel drug delivery system. 2nd edn, Chapter 7. .Marcel Decker, New York.

  1. Hsieh, D.S.(ED) (1994) Drug permeation enhancement. Marcel Decker, New York.

  1. Stoughton RD. Percutaneous absorption.Toxicol Appl Pharmocol 1965;7:1-8

  1. Black C. D. Transdermal DDS. US Pharm 1982; 1:49

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