INTRODUCTION:

Nowadays, the transdermal route has become one of the most successful and innovative focus for research in drug delivery, with around 40% of the drug candidate being under clinical evaluation related to transdermal systems. The technology has a proven record of FDA approval since the first transdermal patch was approved in 1981. The market for transdermal products has been in a significant upward trend and this is likely to continue for the foreseeable future. An increasing number of TDD products continue to deliver real therapeutic benefit to patients around the world.

Drugs can be delivered across the skin to have an effect on the tissues adjacent to the site of application (topical delivery) or to have an effect after distribution through the circulatory system (systemic delivery). While there are many advantages to delivering drugs through the skin, the barrier properties of the skin provide a significant challenge. By understanding the mechanisms by which compounds cross the skin it will be possible to devise means for improving drug delivery.

Some of the many factors that influence the rate of delivery of drugs across the skin include; the thermodynamic activity of the drug in the formulation; the interaction of the drug and the formulation with the skin; variations in skin with age, race, anatomical region and disease. Research in transdermal drug delivery needs to address all of these factors. The highest selling transdermal patch in the United States was the nicotine patch which releases nicotine to help with cessation of tobacco smoking. The first commercially available vapour patch to reduce smoking was approved in Europe in 2007. The patches release essential oils that help the smoker to reduce gradually the number of cigarettes instead of stopping the smoking abruptly. Delivering medicine to the general circulation through the skin is seen as a desirable alternative to taking it by mouth. Patients often forget to take their medicine, and even the most faithfully compliant get tired of swallowing pills, especially if they must take several each day. Additionally, bypassing the gastrointestinal (GI) tract would obviate the GI irritation that frequently occurs and avoid partial first-pass in activation by the liver. Further, steady absorption of drug over hours or days is usually preferable to the blood level spikes and troughs produced by oral dosage forms. These advantages are offered by the currently marketed transdermal products. One of the most successful, the nicotine patch, releases nicotine over sixteen hours, continuously suppressing the smoker’s craving for a cigarette. The scopolamine patch is worn behind the ear and releases the alkaloid for three days, preventing motion sickness without the need to swallow tablets periodically. The fentanyl patch acts for seventy-two hours, providing long-lasting pain relief. And an estrogen–progestin contraceptive patch needs to be applied only once a week, a boon for women who find it onerous to take one pill every day. The Transdermal route is indeed desirable, but there is one small obstacle: whereas the function of the GI tract is to render ingested material suitable for absorption, the skin’s function is to keep things out of the body. The major barrier within the skin is the stratum corneum, the top layer of the epidermis. The stratum corneum consists of keratinized, flattened remnants of once actively dividing epidermal cells. Hygroscopic, but impermeable to water, it behaves as a tough, flexible membrane. The intercellular space is rich in lipids. The stratum corneum is about ten microns thick, but on the palms and soles it ranges up to 600 microns in thickness. Although the stratum corneum is an efficient barrier, some chemical substances are able to penetrate it and to reach the underlying tissues and blood vessels. These “successful” substances are characterized by low molecular weight (≤500 Da), lipophilicity, and effectiveness at low dosage. The largest daily dose of drug in patch form is that of nicotine: twenty-one milligrams Transdermal absorption occurs through a slow process of diffusion driven by the gradient between the high concentration in the delivery system and the zero concentration prevailing in the skin. Thus, the delivery system must be kept in continuous contact with the skin for a considerable time (hours to days).

Definition:

Transdermal drug delivery systems (patches) are dosage forms designed to deliver a therapeutically effective amount of drug across a patient’s skin³ also defined as medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. Actually, transdermal drug delivery is a transport process of drugs through a multi-laminar structure, e.g. from the patch to SC then to the viable epidermis, and finally penetrating into the blood.⁴

The common ingredients which are used for the preparation of tdds are as follows:^3-4

§ Drug: Drug is in direct contact with release liner.

Ex: nicotine, methotrexate and estrogen.

§ Liners: Protects the patch during storage.

Ex: polyester film.

§ Adhesive: Serves to adhere the patch to the skin for systemic delivery of drug.

Ex: acrylates, polyisobutylene, silicones.

§ Permeation enhancers: Controls the release of the drug.

Ex: terpenes, terpenoids, pyrrolidones. Solvents like alcohol, ethanol, methanol. Surfactants like sodium lauryl sulfate, pluronic F127, pluronic F68.

§ Backing layer: Protect patch from outer environment.

Ex: cellulose derivatives, poly vinyl alcohol, polypropylene silicon rubber.

Types of Transdermal Patches^5-10

a) 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 and also responsible for the releasing the drug to the skin. The adhesive layer is surrounded by a temporary liner and a backing.

b) Multi -layer drug in adhesive:

This type is also similar to the single layer but it contains a 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 the drug. This patch also has a temporary liner-layer and a permanent backing.

c) Vapour patch:

In this type of patch the role of adhesive layer not only serves to adhere the various layers together but also serves volume as release vapour. The vapour patches are new to the market, commonly used for releasing of essential oils in decongestion. Various other types of vapour patches are also available in the market which are used to improve the quality of sleep and reduces the cigarette smoking conditions.

d) Reservoir system:

In this system the drug reservoir is embedded between an impervious backing layer and a 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.

e) 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 (in the case of hot-melt adhesives) 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.

f) Microreservoir 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.

Advantages of transdermal drug delivery systems¹¹

Delivery via the transdermal route is an interesting option because transdermal route is convenient and safe. The positive features of delivery drugs across the skin to achieve systemic effects are:

§ Avoidance of first pass metabolism.

§ Avoidance of gastro intestinal incompatibility.

§ Predictable and extended duration of activity.

§ Minimizing undesirable side effects.

§ Provides utilization of drugs with short biological half lives, narrow therapeutic window.

§ Improving physiological and pharmacological response.

§ Avoiding the fluctuation in drug levels.

§ Inter and intra patient variations.

§ Maintain plasma concentration of potent drugs.

§ Termination of therapy is easy at any point of time.

§ Greater patient compliance due to elimination of multiple dosing profile.

§ Ability to deliver drug more selectively to a specific site.

§ Provide suitability for self administration.

§ Enhance therapeutic efficacy.

Limitations of transdermal drug delivery systems¹¹

§ Transdermal delivery is neither practical nor affordable when required to deliver large doses of drugs through skin.

§ Cannot administer drugs that require high blood levels.

§ Drug of drug formulation may cause irritation or sensitization.

§ Not practical, when the drug is extensively metabolized in the skin and when molecular size is great enough to prevent the molecules from diffusing through the skin.

§ Not suitable for a drug, which doesn’t possess a favourable, o/w partition coefficient.

§ The barrier functions of the skin of changes from one site to another on the same person, from person to person and with age.

Kinetics of transdermal permeation:

Skin permeation kinetics is vital to the development of TDDS. Simple diffusion laws can be used to describe the percutaneous absorption process. In TDDS, it is assumed that steady-state conditions reached and thus it follows fick’s first law of diffusion¹², mathematically expressed as: J= KD (C0-Ci)/h

J= flux per unit area, K= partition coefficient of permeant and D is its diffusion coefficient in the stratum corneum of path length h, C0 and Ci are concentrations of permeant on skin and in the body respectively, generally C0 is much greater than Ci , this simplifies the above equation to: J= KDC0/h

Pathways for a drug molecule to transverse stratum corneum:

The stratum corneum of epidermis is the main barrier for traversing drug molecule from TDDS.

1. Transappendageal transport (shunt route transport): In this pathway the appendages (hair follicles, sweat ducts) offer pores that bypass the barrier of the stratum corneum. However, these openings onto the skin surface occupy only around 0.1% of the total skin surface area.⁸The shunt routes may be important for ions and large polar molecules that struggle to cross intact stratum corneum.⁹

2. Intracellular route (transcellular): The pathway is directly across the stratum corneum¹¹and the molecule crossing the intact stratum corneum faces numerous repeating hurdles. First, there is partitioning into the keratinocyte, followed by diffusion through the hydrated keratin. In order to leave the cell, the molecule must partition into the bilayer lipids before diffusing across the lipid bilayer to the next keratinocyte. For highly hydrophilic molecules the transcellular route may be predominant.

3. Intercellular route: In this rout the pathway is via lipid matrix between the keratinocytes. It is now accepted that this route provides the principle pathway by which most small, uncharged molecules traverse stratum corneum.

Various methods for preparation of TDDS:

a. Asymmetric TPX membrane method¹³

A prototype patch can be fabricated for this a heat sealable polyester film (type 1009, 3m) with a concave of 1cm diameter will be used as the backing membrane. Drug sample is dispensed into the concave membrane, covered by a TPX {poly (4-methyl-1-pentene)} asymmetric membrane, and sealed by an adhesive.

[(Asymmetric TPX membrane preparation):

These are fabricated by using the dry/wet inversion process. TPX is dissolved in a mixture of solvent (cyclohexane) and nonsolvent additives at 60°c to form a polymer solution. The polymer solution is kept at 40°C for 24 hrs and cast on a glass plate to a pre-determined thickness with a gardener knife. After that the casting film is evaporated at 50°C for 30 sec, then the glass plate is to be immersed immediately in coagulation bath [maintained the temperature at 25°C]. After 10 minutes of immersion, the membrane can be removed, air dry in a circulation oven at 50°C for 12 hrs]

b. Circular teflon mould method¹⁴

Solutions containing polymers in various ratios are used in an organic solvent. Calculated amount of drug is dissolved in half the quantity of same organic solvent. Enhancers in different concentrations are dissolved in the other half of the organic solvent and then added. Di-N-butyl phthalate is added as a plasticizer into drug polymer solution. The total contents are to be stirred for 12 hrs and then poured into a circular teflon mould. The moulds are to be placed on a leveled surface and covered with inverted funnel to control solvent vaporization in a laminar flow hood model with an air speed of 0.5 m/s. The solvent is allowed to evaporate for 24 hrs. The dried films are to be stored for another 24 hrs at 25±0.5°C in a desiccators containing silica gel before evaluation to eliminate aging effects. The type films are to be evaluated within one week of their preparation.

c. Mercury substrate method¹⁵

In this method drug is dissolved in polymer solution along with plasticizer. The above solution is to be stirred for 10- 15 minutes to produce a homogenous dispersion and poured in to a leveled mercury surface, covered with inverted funnel to control solvent evaporation.

d. By using “IPM membranes” method ¹⁶

In this method drug is dispersed in a mixture of water and propylene glycol containing carbomer 940 polymer and stirred for 12 hrs in magnetic stirrer. The dispersion is to be neutralized and made viscous by the addition of triethanolamine. Buffer pH 7.4 can be used in order to obtain solution gel, if the drug solubility in aqueous solution is very poor. The formed gel will be incorporated in the IPM membrane.

e. By using “EVAC membranes” method ¹⁷

In order to prepare the target transdermal therapeutic system, 1% carbopol reservoir gel, polyethelene (PE), ethylene vinyl acetate copolymer (EVAC) membranes can be used as rate control membranes. If the drug is not soluble in water, propylene glycol is used for the preparation of gel. Drug is dissolved in propylene glycol, carbopol resin will be added to the above solution and neutralized by using 5% w/w sodium hydroxide solution. The drug (in gel form) is placed on a sheet of backing layer covering the specified area. A rate controlling membrane will be placed over the gel and the edges will be sealed by heat to obtain a leak proof device.

f. Aluminium backed adhesive film method ¹⁸

Transdermal drug delivery system may produce unstable matrices if the loading dose is greater than 10 mg. Aluminium backed adhesive film method is a suitable one. For preparation of same, chloroform is choice of solvent, because most of the drugs as well as adhesive are soluble in chloroform. The drug is dissolved in chloroform and adhesive material will be added to the drug solution and dissolved. A custammade aluminium former is lined with aluminium foil and the ends blanked off with tightly fitting cork blocks.

g. Preparation of TDDS by using Proliposomes ^{19, 20}

The proliposomes are prepared by carrier method using film deposition technique. From the earlier reference drug and lecithin in the ratio of 0.1:2.0 can be used as an optimized one. The proliposomes are prepared by taking 5mg of mannitol powder in a 100mL round bottom flask which is kept at 60-70°c temperature and the flask is rotated at 80-90 rpm and dried the mannitol at vacuum for 30 minutes. After drying, the temperature of the water bath is adjusted to 20-30°C. Drug and lecithin are dissolved in a suitable organic solvent mixture, a 0.5mL aliquot of the organic solution is introduced into the round bottomed flask at 37°C, after complete drying second aliquots (0.5mL) of the solution is to be added. After the last loading, the flask containing proliposomes are connected in a lyophilizer and subsequently drug loaded mannitol powders (proliposomes) are placed in a desiccator over night and then sieved through 100 mesh. The collected powder is transferred into a glass bottle and stored at the freeze temperature until characterization.

h. By using free film method²¹

Free film of cellulose acetate is prepared by casting on mercury surface. A polymer solution 2% w/w is to be prepared by using chloroform. Plasticizers are to be incorporated at a concentration of 40% w/w of polymer weight. Five ml of polymer solution was poured in a glass ring which is placed over the mercury surface in a glass petridish. The rate of evaporation of the solvent is controlled by placing an inverted funnel over the petridish. The film formation is noted by observing the mercury surface after complete evaporation of the solvent. The dry film will be separated out and stored between the sheets of wax paper in a desiccator until use. Free films of different thickness can be prepared by changing the volume of the polymer solution.

Evaluation parameters Interaction studies²²

Excipients are integral components of almost all pharmaceutical dosage forms. The stability of a formulation amongst other factors depends on the compatibility of the drug with the excipients. The drug and the excipients must be compatible with one another to produce a product that is stable, thus it is mandatory to detect any possible physical or chemical interaction as it can affect the bioavailability and stability of the drug. If the excipients are new and have not been used in formulations containing the active substance, the compatibility studies play an important role in formulation development. Interaction studies are commonly carried out in thermal analysis, FTIR, UV and chromatographic techniques by comparing their physicochemical characters such as assay, melting endotherms, characteristic wave numbers, absorption maxima etc.,

Thickness of the patch²²

The thickness of the drug loaded patch is measured in different points by using a digital micrometer and determines the average thickness and standard deviation for the same to ensure the thickness of the prepared patch.

Weight uniformity²²

The prepared patches are to be dried at 60°C for 4 hour before testing. A specified area of patch is to be cut in different parts of the patch and weigh in digital balance. The average weight and standard deviation values are to be calculated from the individual weights.

Folding endurance²²

A strip of specific area is to be cut evenly and repeatedly folded at the same place till it broke. The number of times the film could be folded at the same place without breaking gave the value of the folding endurance.

Percentage moisture content²²

The prepared films are to be weighed individually and to be kept in a desiccator containing fused calcium chloride at room temperature for 24 hour. After 24 hour the films are to be reweighed and determine the percentage moisture content from the below mentioned formula:

Percentage moisture content = [initial weight- final weight/ final weight] × 100.

Percentage moisture uptake²²

The weighed films are to be kept in a desiccator at room temperature for 24 hour containing saturated solution of potassium chloride in order to maintain 84% RH. After 24 hour the films are to be reweighed and determine the percentage moisture uptake from the below mentioned formula:

Percentage moisture uptake = [final weight- initial weight/ initial weight] × 100.

Water vapour permeability (WVP) evaluation²²

Water vapour permeability can be determined with foam dressing method the air forced oven is replaced by a natural air circulation oven. The WVP can be determined by the following formula:

WVP=W/A

Where, WVP is expressed in gm/m² per 24 hour,

W is the amount of vapour permeated through the patch expressed in gm/24 hour and A is the surface area of the exposure samples expressed in m².

Drug content:²²

A specified area of patch is to be dissolved in a suitable solvent in specific volume. Then the solution is to be filtered through a filter medium and analyze the drug contain with the suitable method (UV or HPLC technique). Each value represents average of three different samples.

Uniformity of dosage unit test:²²

An accurately weighed portion of the patch is to be cut into small pieces and transferred to a specific volume volumetric flask, dissolved in a suitable solvent and sonicate for complete extraction of drug from the patch and made up to the mark with same. The resulting solution was allowed to settle for about an hour, and the supernatant was suitably diluted to give the desired concentration with suitable solvent. The solution was filtered using 0.2 µm membrane filter and analyzed by suitable analytical technique (UV or HPLC) and the drug content per piece will be calculated.

Polariscope examination:²²

This test is to be performed to examine the drug crystals from patch by polariscope. A specific surface area of the piece is to be kept on the object slide and observe for the drugs crystals to distinguish whether the drug is present as crystalline form or amorphous form in the patch.

Shear adhesion test²²

This test is to be performed for the measurement of the cohesive strength of an adhesive polymer. It can be influenced by the molecular weight, the degree of cross linking and the composition of polymer, type and the amount of tackifier added. An adhesive coated tape is applied onto a stainless steel plate; a specified weight is hung from the tape, to affect it pulling in a direction parallel to the plate. Shear adhesion strength is determined by measuring the time it takes to pull the tape off the plate. The longer the time take for removal, greater is the shear strength.

Peel adhesion test²²

In this test, the force required to remove an adhesive coating form a test substrate is referred to as peel adhesion. Molecular weight of adhesive polymer, the type and amount of additives are the variables that determined the peel adhesion properties. A single tape is applied to a stainless steel plate or a backing membrane of choice and then tape is pulled from the substrate at a 180º angle, and the force required for tape removed is measured.

Thumb tack test²²

It is a qualitative test applied for tack property determination of adhesive. The thumb is simply pressed on the adhesive and the relative tack property is detected.

Flatness test²²

Three longitudinal strips are to be cut from each film at different portion like one from the centre, other one from the left side, and another one from the right side. The length of each strip is measured and the variation in length because of non-uniformity in flatness is measured by determining percent constriction, with 0% constriction equivalent to 100% flatness.

Percentage elongation break test²²

The percentage elongation break is to be determined by noting the length just before the break point, the percentage elongation can be determined from the below mentioned formula:

Elongation percentage = L1-L2 × 100 L2

Where, L1is the final length of each strip and L2 is the initial length of each strip.

Rolling ball tack test²²

This test measures the softness of a polymer that relates to talk. In this test, stainless steel ball of 7/16 inches in diameter is released on an inclined track so that it rolls down and comes into contact with horizontal, upward facing adhesive. The distance the ball travels along the adhesive provides the measurement of tack, which is expressed in inch.

Quick stick (peel-tack) test²²

In this test, the tape is pulled away from the substrate at 90ºC at a speed of 12 inches/min. The peel force required to break the bond between adhesive and substrate is measured and recorded as tack value, which is expressed in ounces or grams per inch width.

Probe tack test²²:

In this test, the tip of a clean probe with a defined surface roughness is brought into contact with adhesive, and when a bond is formed between probe and adhesive. The subsequent removal of the probe mechanically breaks it. The force required to pull the probe away from the adhesive at fixed rate is recorded as tack and it is expressed in grams.

In vitro drug release studies²²

The paddle over disc method (USP apparatus V) can be employed for assessment of the release of the drug from the prepared patches. Dry films of known thickness is to be cut into definite shape, weighed, and fixed over a glass plate with an adhesive. The glass plate was then placed in a 500 mL of the dissolution medium or phosphate buffer ( pH 7.4), and the apparatus was equilibrated to 32± 0.5°C. The paddle was then set at a distance of 2.5 cm from the glass plate and operated at a speed of 50 rpm. Samples (5 mL aliquots) can be withdrawn at appropriate time intervals up to 24 hour and analyzed by UV spectrophotometer or HPLC. The experiment is to be performed in triplicate and the mean value can be calculated.

In vitro skin permeation studies²²

An in vitro permeation study can be carried out by using diffusion cell. Full thickness of abdominal skin of male wistar rats weighing 200 to 250 gm. Hair from the abdominal region is to be removed carefully by using a electric clipper; the dermal side of the skin was thoroughly cleaned with distilled water to remove any adhering tissues or blood vessels, equilibrated for an hour in dissolution medium or phosphate buffer pH 7.4 before starting the experiment and was placed on a magnetic stirrer with a small magnetic needle for uniform distribution of the diffusant. The temperature of the cell was maintained at 32 ± 0.5°C using a thermostatically controlled heater. The isolated rat skin piece is to be mounted between the compartments of the diffusion cell, with the epidermis facing upward into the donor compartment. Sample volume of definite volume is to be removed from the receptor compartment at regular intervals, and an equal volume of fresh medium is to be replaced. Samples are to be filtered through filtering medium and can be analyzed spectrophotometrically or HPLC. Flux can be determined directly as the slope of the curve between the steady-state values of the amount of drug permeated (mg cm²) vs. time in hours and permeability coefficients were deduced by dividing the flux by the initial drug load (mg cm²).

Skin irritation study²²

Skin irritation and sensitization testing can be performed on healthy rabbits (average weight 1.2 to 1.5 kg). The dorsal surface (50 cm²) of the rabbit is to be cleaned and remove the hair from the clean dorsal surface by shaving and clean the surface by using rectified spirit and the representative formulations can be applied over the skin. The patch is to be removed after 24 hour and the skin is to be observed and classified into 5 grades on the basis of the severity of skin injury.

Stability studies²²

Stability studies are to be conducted according to the ICH guidelines by storing the TDDS samples at 40±0.5°C and 75±5% RH for 6 months. The samples were withdrawn at 0, 30, 60, 90 and 180 days and analyze suitably for the drug content.

Hardness⁸

Performing the test on different three patches individually from each batch by fabricated hardness instrument and the average was calculated.

Tensile strength⁶

Tensile strength of the film was determined with modifed tensile tester (manish patel et al.). Tensile strength is expressed as follows:

Tensile strength = Tensile load at break / Cross section area.

Surface pH⁸

Surface pH of the patch was determined by allowing them to swell in closed petridish at room temperature for 30 minutes in 0.1 mL of double distilled water. The swollen devices were removed and placed under digital pH meter to determine the surface pH.

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Received on 29.03.2012 Modified on 05.04.2012

Research J. Pharm. and Tech. 5(6): June 2012; Page 757-763