Transdermal drug delivery system
Transdermal drug delivery system includes all topically administered drug formulations intended to deliver the active ingredients into the circulation. They provide controlled continuous delivery of drugs through the skin to the systemic circulation. The drug is mainly delivered through the skin with the aid of transdermal patch. A Transdermal patch is a medicament adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. A drug is applied in a relatively high dose to the inside of a patch, which is worn on the skin for an extended period of time. Through a diffusion process, the drug enters the bloodstream directly through the skin.
Anatomy and physiology of skin
Human skin comprises of three distinct but mutually dependent tissues (Tortora and Grabowski, 2006; Wilson and Waugh, 1996), namely:
1. The stratified, a vascular, cellular Epidermis;
2. Underlying dermis of connective tissues and;
3. Hypodermis.
1.Epidermis
The multilayered envelop of the epidermis varies in thickness, depending on cell size and number of cell layers, ranging from 0.8 mm on palms and soles down to 0.06 mm on the eyelids. Stratum corneum and the remainder of the epidermis, also called viable epidermis, cover a major area of skin .
Stratum corneum:
This is the outermost layer of skin, also called horney layer. It is approximately 10 mm thick when dry but swells to several times this thickness when fully hydrated. It contains 10 to 25 layers of parallel to the skin surface, lying dead, keratinized cells, called corneocytes. It is flexible but relatively impermeable. The stratum corneum is the principal barrier for penetration. The barrier nature of the horney layer depends critically on its constituents: 75 to 80% proteins, 5 to 15% lipids, and 5 to 10% ondansetron material on a dry weight basis. Protein fractions predominantly contain alpha-keratin (70%) with some beta-keratin (10%) and cell envelope (5%). Lipid constituents vary with body site (neutral lipids, sphingolipids, polar lipids, cholesterol). Phospholipids are largely absent, a unique feature of mammalian membrane.
Viable epidermis: This is situated beneath the stratum corneum and varies in thickness from 0.06 mm on the eyelids to 0.8 mm on the palms. Going inwards, it consists of various layers as stratum lucidum, stratum granulosum, stratum spinosum, and the stratum basale. In the basale layer, mitosis of the cells constantly renews the epidermis and this proliferation compensates the loss of dead horney cells from the skin surface. As the cells produced by the basale layer move outward, they alter morphologically and histochemically, undergoing keratinization to form the outermost layer of stratum corneum (Tortora and Grabowski, 2006; Wilson and Waugh, 1996).
2.Dermis
Dermis is a 3 to 5 mm thick layer and is composed of a matrix of connective tissue which contains blood vessels, lymph vessels, and nerves. The continuous blood supply has essential function in regulation of body temperature. It also provides nutrients and oxygen to the skin while removing toxins and waste products. Capillaries reach to within 0.2 mm of skin surface and provide sink conditions for most molecules penetrating the skin barrier. The blood supply thus keeps the dermal concentration of permeate very low, and the resulting concentration difference across the epidermis provides the essential driving force for transdermal permeation (Tortora and Grabowski, 2006; Wilson and Waugh, 1996).
3.Hypodermis
The hypodermis or subcutaneous fat tissue supports the dermis and epidermis. It serves as a fat storage area. This layer helps to regulate temperature, provides nutritional support and mechanic protection. It carries principal blood vessels and nerves to skin and may contain sensory pressure organs.
For transdermal drug delivery, the drug has to penetrate through all these three layers and reach into systemic circulation while in case of topical drug delivery, only penetration through stratum corneum is essential and then retention of drug in skin layers is desired.
ROUTES OF PENETRATION
The diffusant has two potential entry routes to the blood vasculature; through the epidermis itself or diffusion through shunt pathway, mainly hair follicles with their associated sebaceous glands and the sweat ducts.
Therefore, there are two major routes of penetration (Bodde et al., 1991; Heisig et al., 1996).
Transcorneal penetration
- Intracellular penetration
Drug molecule passes through the cells of the stratum corneum. It is generally seen in case of hydrophilic drugs. As stratum corneum hydrates, water accumulates near the outer surface of the protein filaments. Polar molecules appear to pass through this immobilized water.
- Intercellular penetration
Non-polar substances follow the route of intercellular penetration. These molecules dissolve in and diffuse through the non- aqueous lipid matrix imbibed between the protein filaments.
- Transappendageal penetration
This is also called as the shunt pathway (Bodde et al., 1991; Heisig et al., 1996).
In this route, the drug molecule may transverse through the hair follicles, the sebaceous pathway of the pilosebaceous apparatus or the aqueous pathway of the salty sweat glands (Barry, 1987). The transappendageal pathway is considered to be of minor importance because of its relatively smaller area (less than 0.1% of total surface). However this route may be of some importance for large polar compounds.
The route through which permeation occurs is largely dependent on physico-chemical characteristics of penetrant, most importantly being the relative ability to partition into each skin phase. 
The transdermal permeation can be visualized as composite of a series in sequence as:
1. Adsorption of a penetrant molecule onto the surface layers of stratum corneum.
2. Diffusion through stratum corneum and through viable epidermis.
3. Finally through the papillary dermis into the microcirculation.
BASIC COMPONENTS OF TDDS:
1. The drug
2. Polymer matrix
3. Permeation enhancers
4. Adhesive
5. Backing layer.
1. DRUG
The drug is in direct contact with release liner. Ex: Nicotine, Methotrexate, and Oestrogen. Some of the desirable properties of a drug for transdermal delivery:
1. The drug molecule should possess an adequate solubility in oil and water.
2. The drug should have a molecular weight less than approximately 1000 daltons.
3. The drug should have low melting point.
4. The drug molecule would require a balanced partition coefficient to penetrate the stratum corneum.
2. POLYMER MATRIX
These polymers control the release of the drug from the drug reservoir.
Natural polymers: shellac, gelatin, waxes, gums, starch etc.,
Synthetic polymers: polyvinyl alcohol, polyamide, polyethylene, polypropylene, Polyurea, polymethylmethacrylate etc.
3. PERMEATION ENHANCERS:
Substances exist which temporarily diminish the impermeability of the skin are known as accelarants or sorption promoters or penetration enhancers.
These include water, pyrolidones, fatty acids and alcohols, azone and its derivatives, alcohols and glycols, essential oils, terpenes and derivatives, sulfoxides like dimethyl sulfoximide and their derivatives, urea and surfactants.
Surfactants are proposed to enhance polar pathway transport especially of hydrophilic drugs. The ability of a surfactant to alter penetration is a function of the polar head group and the hydrocarbon chain length.
Anionic surfactants: sodium lauryl sulphate, Decodecylmethyl sulphoxide etc.,
Nonionic surfactants: Pluronic F 127, Pluronio F68, etc.,
Enhancer actions can be classified by lipid-protein partitioning concept.
This hypothesis suggests that enhancers act by one or more ways selected from three main possibilities.
Lipid action
The enhancer interacts with the organized intracellular lipid structure of the stratum corneum so as to disrupt it and make it more permeable to drug molecules. Very many enhancers operate in this way. Some solvents act by extracting the lipid Components and thus make the horny layer more permeable.
Protein modification
Ionic surface active molecules in particular tend to interact well with the keratin in the corneocytes, to open up the dense keratin structure and make it more permeable. The intracellular route is not usually prominent in drug permeation, although drastic reductions to this routes resistance could open up an alternative path for drug penetration. Partitioning promotion
Many solvents can enter the stratum corneum, change its solvent properties and thus increase the partitioning of a second molecule into the horny layer. This molecule may be a drug, a coenhancer or a cosolvent.
For example ethanol has been used to increase the penetration of the drug molecules nitroglycerin and estradiol.
4. ADHESIVE
Serves to adhere the patch to the skin for systemic delivery of drug. Ex: Silicones, Polyisobutylene.
5. BACKING LAYER
Backing layer protects patch from outer environment.
Ex: Cellulose derivatives, Polypropylene silicon rubber.
Care taken while applying transdermal patch
(1)The part of the skin where the patch is to be applied should be properly cleaned.
(2) Patch should not be cut because cutting the patch destroys the drug delivery system.
(3) Before applying a new patch it should be made sure that the old patch is removed from the site.
(4) Care should be taken while applying or removing the patch because anyone handling the patch can absorb the drug from the patch.
(5) The patch should be applied accurately to the site of administration.
Factors affecting transdermal bioavailability
Two major factors affect the bioavailability of the drug via transdermal routes:
(1)Physiological factors
(2) Formulation factors
1 Physiological factors include
(1)Stratum corneum layer of the skin
(2) Anatomic site of application on the body
(3) Skin condition and disease
(4) Age of the patient
(5) Skin metabolism
(6) Desquamation (peeling or flaking of the surface of the skin)
(7) Skin irritation and sensitization (8) Race
2. Formulation factors include
(1)Physical chemistry of transport
(2) Vehicles and membrane used
(3) Penetration enhancers used
(4) Method of application
(5) Device used
Mechanism of Action of Transdermal Patch
The application of the transdermal patch and the flow of the active drug constituent from the patch to the circulatory system via skin occur through various methods.
1. Iontophoresis
Iontophoresis passes a few milliamperes of current to a few square centimeters of skin through the electrode placed in contact with the formulation, which facilitates drug delivery across the barrier. Mainly used of pilocarpine delivery to induce sweating as part of cystic fibrosis diagnostic test. Iontophoretic delivery of lidocaine appears to be a promising approach for rapid onset of anesthesia.
2. Electroporation
Electroporation is a method of application of short, high-voltage electrical pulses to the skin. After electroporation, the permeability of the skin for diffusion of drugs is increased by 4 orders of magnitude. The electrical pulses are believed to form transient aqueous pores in the stratum corneum, through which drug transport occurs. It is safe and the electrical pulses can be administered painlessly using closely spaced electrodes to constrain the electric field within the nerve-free stratum corneum.
3. Application by ultrasound
Application of ultrasound, particularly low frequency ultrasound, has been shown to enhance transdermal transport of various drugs including macromolecules. It is also known as sonophoresis. Katz et al. reported on the use of low-frequency sonophoresis for topical delivery of EMLA cream.
4. Use of microscopic projection
Transdermal patches with microscopic projections called microneedles were used to facilitate transdermal drug transport. Needles ranging from approximately 10-100 µm in length are arranged in arrays. When pressed into the skin, the arrays make microscopic punctures that are large enough to deliver macromolecules, but small enough that the patient does not feel the penetration or pain. The drug is surface coated on the microneedles to aid in rapid absorption. They are used in development of cutaneous vaccines for tetanus and influenza.
5.Various other methods are
thermal poration, magnetophoresis, and photomechanical waves.
Types of Transdermal Patch
1. Single-layer Drug-in-Adhesive
The adhesive layer of this system also contains the drug. In this type of patch the adhesive layer not only serves to adhere the various layers together, along with the entire system to the skin, but is also responsible for the releasing of the drug. The adhesive layer is surrounded by a temporary liner and a backing.
2. Multi-layer Drug-in-Adhesive
The multi-layer drug-in adhesive patch is similar to the single-layer system in that both adhesive layers are also responsible for the releasing of the drug. The multi-layer system is different however that it adds another layer of drug-in-adhesive, usually separated by a membrane (but not in all cases). This patch also has a temporary liner-layer and a permanent backing.
3. Reservoir
Unlike the Single-layer and Multi-layer Drug-in adhesive systems the reservoir transdermal system has a separate drug layer. The drug layer is a liquid compartment containing a drug solution or suspension separated by the adhesive layer. This patch is also backed by the backing layer. In this type of system the rate of release is zero order.
4. Matrix
The Matrix system has a drug layer of a semisolid matrix containing a drug solution or suspension. The adhesive layer in this patch surrounds the drug layer partially overlaying it.
5. Vapour Patch
In this type of patch the adhesive layer not only serves to adhere the various layers together but also to release vapour. The vapour patches are new on the market and they release essential oils for up to 6 hours. The vapours patches release essential oils and are used in cases of congestion mainly. Other vapour patches on the market are controller vapour patches that improve the quality of sleep. Vapour patches that reduce the quantity of cigarettes that one smokes in a month are also available on the market.
Evaluation of Transdermal Patches
- Physicochemical evaluation
- In vitro evaluation
- In vivo evaluation
1. Physicochemical Evaluation:
- Thickness:
The thickness of transdermal film is determined by travelling microscope, dial gauge, screw gauge or micrometer at different points of the film.
- Uniformity of weight:
Weight variation is studied by individually weighing 10 randomly selected patches and calculating the average weight. The individual weight should not deviate significantly from the average weight.
- Drug content determination:
An accurately weighed portion of film (about 100 mg) is dissolved in 100 mL of suitable solvent in which drug is soluble and then the solution is shaken continuously for 24 h in shaker incubator. Then the whole solution is sonicated. After sonication and subsequent filtration, drug in solution is estimated spectrophotometrically by appropriate dilution.
- Content uniformity test:
10 patches are selected and content is determined for individual patches. If 9 out of 10 patches have content between 85% to 115% of the specified value and one has content not less than 75% to 125% of the specified value, then transdermal patches pass the test of content uniformity. But if 3 patches have content in the range of 75% to 125%, then additional 20 patches are tested for drug content. If these 20 patches have range from 85% to 115%, then the transdermal patches pass the test.
- Moisture content:
The prepared films are weighed individually and kept in a desiccators containing calcium chloride at room temperature for 24 h. The films are weighed again after a specified interval until they show a constant weight. The percent moisture content is calculated using following formula.
% Moisture content = Initial weight – Final weight X 100
- Moisture Uptake:
Weighed films are kept in a desiccator at room temperature for 24 h. These are then taken out and exposed to 84% relative humidity using saturated solution of Potassium chloride in a desiccator until a constant weight is achieved. % moisture uptake is calculated as given below.
% moisture uptake = Final weight – Initial weight X 100
- Flatness:
A transdermal patch should possess a smooth surface and should not constrict with time. This can be demonstrated with flatness study. For flatness determination, one strip is cut from the centre and two from each side of patches. The length of each strip is measured and variation in length is measured by determining percent constriction. Zero percent constriction is equivalent to 100 percent flatness.
% constriction = I1 – I2 X 100 I2 = Final length of each strip I1 = Initial length of each strip
- Folding Endurance:
Evaluation of folding endurance involves determining the folding capacity of the films subjected to frequent extreme conditions of folding. Folding endurance is determined by repeatedly folding the film at the same place until it break. The number of times the films could be folded at the same place without breaking is folding endurance value.
- Tensile Strength:
To determine tensile strength, polymeric films are sandwiched separately by corked linear iron plates. One end of the films is kept fixed with the help of an iron screen and other end is connected to a freely movable thread over a pulley. The weights are added gradually to the pan attached with the hanging end of the thread. A pointer on the thread is used to measure the elongation of the film. The weight just sufficient to break the film is noted. The tensile strength can be calculated using the following equation. Tensile strength= F/a.b (1+L/l) F is the force required to break; a is width of film; b is thickness of film; L is length of film; l is elongation of film at break point.
- Tack properties:
It is the ability of the polymer to adhere to substrate with little contact pressure. Tack is dependent on molecular weight and composition of polymer as well as on the use of tackifying resins in polymer.
- Thumb tack test:
The force required to remove thumb from adhesive is a measure of tack.
Rolling ball test: This test involves measurement of the distance that stainless steel ball travels along an upward facing adhesive. The less tacky the adhesive, the further the ball will travel.
- Quick stick (Peel tack) test:
The peel force required breaking the bond between an adhesive and substrate is measured by pulling the tape away from the substrate at 90? at the speed of 12 inch/min. Probe tack test: Force required to pull a probe away from an adhesive at a fixed rate is recorded as tack.
2. In vitro release studies:
- a. The Paddle over Disc: (USP apparatus 5/ PhEur 2.9.4.1)
This method is identical to the USP paddle dissolution apparatus, except that the transdermal system is attached to a disc or cell resting at the bottom of the vessel which contains medium at 32 ±5°C.
- b. The Cylinder modified USP Basket: (USP apparatus 6 / PhEur 2.9.4.3)
This method is similar to the USP basket type dissolution apparatus, except that the system is attached to the surface of a hollow cylinder immersed in medium at 32 ±5°C.
- c. The reciprocating disc: (USP apparatus 7)
In this method patches attached to holders are oscillated in small volumes of medium, allowing the apparatus to be useful for systems delivering low concentration of drug. In addition paddle over extraction cell method (PhEur 2.9.4.2) may be used.
