About Authors:
Patel Chirag J1*, Satyanand Tyagi2, Patel Jaimin1
1Maharishi Arvind Institute of Pharmacy, Department of Pharmaceutics, Jaipur, Rajasthan.
2President, Tyagi Pharmacy Association & Scientific Writer (Pharmacy), Chattarpur, New Delhi, India.
*chirag.bangalore@gmail.com, +918000501871
ABSTRACT:
Now a day about 74% of drugs are taken orally and are found not to be as effective as desired either due to bioavailability problems or degradation of drug in acidic pH of stomach. To resolve such problems, transdermal drug delivery system (TDDS) was emerged. Transdermal drug delivery systems are dosage forms involves drug transport to viable epidermal and dermal tissues of the skin for local therapeutic effect while a very major fraction of drug is transported into the systemic blood circulation. Transdermal drug delivery systems, also known as ‘‘patches,’’ are dosage forms designed to deliver a therapeutically effective amount of drug across a patient’s skin. This review article provides an overview of TDDS, advantages, limitations, various components of TDDS, methods of preparation, types of transdermal patches, factors affecting transdermal permeation, evaluation parameters and new approaches in TDDS.
Reference Id: PHARMATUTOR-ART-1500
INTRODUCTION:
TDDS can provide some desirable performances over conventional pharmaceutical dosage formulations, such as avoiding gut and hepatic first-pass metabolism, improving drug bioavailability, reducing dose frequency and stabilizing drug delivery profiles [1-2]. Drug delivery with transdermal patch systems exhibit slow, controlled drug release and absorption. The plasma drug concentration does not vary significantly over time. Transdermal delivery system is a growing market that is expected to expand in the near future with the discovery of new drug treatment applications and technologies. Transdermal drug delivery system can be defined as the delivery of drugs through intact skin to reach systemic circulation in sufficient quantity to administer a therapeutic dose [3-4]. Transdermal delivery provides a leading edge over injectables and oral routes by increasing patient compliance and avoiding first pass metabolism respectively [5]. Transdermal delivery not only provides controlled, constant administration of the drug, but also allows continuous input of drugs with short biological half-lives and eliminates pulsed entry into systemic circulation, which often causes undesirable side effects. Thus various forms of Novel drug delivery system such as Transdermal drug delivery systems, Controlled release systems, Transmucosal delivery systems etc. emerged. Several important advantages of transdermal drug delivery are limitation of hepatic first pass metabolism, enhancement of therapeutic efficiency and maintenance of steady plasma level of the drug. The first Transdermal system, Transderm-SCOP was approved by FDA in 1979 for the prevention of nausea and vomiting associated with travel, particularly by sea. The evidence of percutaneous drug absorption may be found through measurable blood levels of the drug, detectable excretion of the drug and its metabolites in the urine and through the clinical response of the patient to the administered drug therapy [6].
ADVANTAGES [7-9]
1. Increased patient compliance due to reduced dosing frequency.
2. Transdermal route bypasses first pass metabolism.
3. Minimizes fluctuations in physiological and pharmacological response.
4. Decreased side effects due to reduced plasma concentration.
5. Ease in self administration.
6. Reduces fluctuations in plasma concentration.
7. Drug candidates with short biological half life and low therapeutic index can be effectively utilized.
8. Avoids fluctuations in drug level.
9. Effect of inter and intra patient variations are minimized.
10. Low melting drugs can be given by this route due to low solubility both in water and fat.
11. Termination of therapy is easy and possible at any time.
LIMITATIONS [7],[10],[11]
1. Drugs with high molecular weight (> 500 Da) are difficult to penetrate the stratum corneum.
2. Drug dose is a limiting factor.
3. Drugs with partition coeffeicients in either of the extremities (low or high) fail to reach the systemic circulation.
4. Bioavailability of a drug through transdermal route is greatly reduced for the drugs which get metabolized in liver.
5. Skin permeability is also a limiting factor.
6. Drugs requiring higher blood levels are difficult to formulate as transdermal drug delivery systems.
7. May lead to skin irritation and allergic response.
BASIC COMPONENTS OF TRANSDERMAL DRUG DELIVERY SYSTEMS
1. Polymer matrix [7]
Release of drug from transdemal drug delivery system is essentially controlled by polymer. As the concentration of polymer is increased, a denser matrix is formed thereby giving slow drug release rate. Conversely, on decreasing the polymer concentration, a lesser dense matrix is formed ensuring a higher release rate. Different classes of polymers have been used to achieve desired release rate for controlled drug delivery. The mechanism of drug release is usually diffusion across the polymeric matrix and rate of drug release depends upon the physicochemical properties and concentration of the drug and polymer used in the preparation of device.
The following are the ideal properties of a polymer to be used in a transdermal drug delivery system:
1. The polymer should be inert i.e., it should not react with the drug
2. The polymer should permit the fabrication of device with a large amount of drug.
3. The polymer must not decompose in the presence of drug and other excipients used in the formulation under storage conditions or conditions of device usage.
4. Polymer must not affect the stability of the drug.
5. There should not be any change in mechanical properties of polymer when large amount of drug is incorporated into it.
6. Polymer should be inexpensive.
7. Polymer should be easily fabricated into the desired device without expensive or complicated chemical or physical treatments.
8. Polymer must maintain its integral properties under the labeled storage conditions for the predetermined duration of shelf life.
9. Polymer must allow diffusion and release of the specific drug. The polymer must not decompose in the presence of drug and other excipients used in the formulation under storage conditions or conditions of device usage.
10. Polymer must not lead to synergistic or antagonistic drug effects.
11. Polymer should be easily available.
12. Polymer should be easy to handle during various steps of manufacturing process.
13. Polymers and its degradation products must be non toxic and non irritant to the skin.
14. Polymer must not produce hypersensitivity reactions.
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Examples of few polymers used:
Different grades of Gelatin, Hydroxy propyl methl cellulose (HPMC), various Gums and their derivatives, Polyvinyl alcohol (PVA), Polyethylene, Polypropylene, Polyvinyl chloride (PVC), Polymethylmethacrylate(PMMA), various grades of Polyvinylpyrrolidone (PVP), Starch, etc.
2. Drug or Active pharmaceutical ingredient (API) [7],[11]
For any transdermal drug delivery system to be a success, drug should be chosen with great care. Drug reservoir is usually in direct contact with the adhesive layer or release liner. Selection of drug candidate for transdermal drug delivery system depends on the physicochemical properties and biological properties of the drug.
Examples: Nicotine, Fentanyl, Nitroglycerine, Methotrexate, Testerone, Estradiol, etc are some of the marketed transdermal drug delivery systems.
The following are the ideal properties of drug to be selected for a transdermal drug delivery system:
Physicochemical properties:
1. Some degree of solubility of drug is essential in both oil and in water (ideally it should be greater than 1 mg/ml). There should be a balance in the lipophilicity and hydrophilicity of the drug. If the drug is highly lipophilic, it would readily permeate the skin but would not be soluble in the fluids found on the skin surface. Bioavailability of such drugs is solubility rate limited. Conversely, if the drug is highly hydrophilic, it would be easily soluble in the fluids found on the layers of the skin but would not readily permeate the skin. Bioavailability of such drug is permeability rate limited.
2. The drug candidate should have melting point less than 200 °F.
Bioavailability of drug from transdermal drug delivery system is directly proportional to the concentration gradient across the membrane which in turn is directly proportional to the log solubility of drug in lipid phase of membrane. Log solubility in turn is inversely proportional to the melting point.
3. Drug with molecular weight less than 1000 Daltons are suitable.
4. Drugs that ionize rapidly at physiological pH are not suitable candidates for transdermal drug delivery systems since ionized particles have poor skin penetration. In such cases, a drug whose saturated aqueous solution has a pH value between 5 and 9 are considered suitable for formulation of transdermal drug delivery system.
5. Number of hydrogen bonding groups in a drug for formulation into transdermal drug delivery systems should be less than 2. This is essential since the number of hydrogen bonding groups is indicative of the polarity of molecule. Less number of hydrogen bonding groups indicates that the molecule is lipophilic.
Biological properties:
1. The drug must have short biological half life.
2. Drug must be potent, i.e., it should be effective in doses of few mgs per day. Ideally it should be less than 25 mg/day.
3. The drug must be non irritant to human skin.
4. The drug must not initiate hypersensitivity reactions.
5. The drug should not degrade when in contact with the skin.
6. Drugs which gets degrade in gastric pH are suitable candidates.
7. Under zero order release conditions, drug must not develop tolerance.
8. Metabolism of drug on skin surface is also a limiting factor.
9. Drugs which undergoes hepatic first pass metabolism are suitable candidates since this route by-passes first pass metabolism.
10. Binding of drug to subcutaneous tissue should not be irreversible.
11. Drugs which lead to toxicity of non-target tissues can be formulated as transdermal drug delivery system.
3. Penetration enhancers [12]
Penetration enhancers are those compounds which enhance the skin permeability by altering the barrier properties of skin to the flux of a drug. These are essential in most of the transdermal formulations.
Flux of drug across skin can be defined as:
J = D [dc/dx]
Where,
D = diffusion coefficient
C = concentration of drug
X = spatial co-ordinate.
The ideal properties of penetration enhancer are:
1. It should not damage the layers of the skin permanently.
2. It should be pharmacologically inert.
3. It should be non toxic.
4. It should be non allergenic.
5. Its action should be specific, reversible and for a specific duration of time. It should not damage the layers of the skin permanently.
6. It should not alter the barrier properties of skin which leads to loss of electrolytes, tissue fluids and other vital components.
7. It should be non-irritating.
A. Surfactants:
These agents are employed for those formulations which contain hydrophilic drugs. These agents enhance polar pathway transport. Percentage increase in penetration enhancement depends on function of polar head group and hydrocarbon chain length. These agents, apart from enhancing penetration also cause skin irritation.
Examples:
a) Cationic surfactants: These are more irritating to skin and hence are not used in transdermal drug delivery systems.
b) Nonionic surfactants: Pluronic F127, Pluronic F68 are some examples of agents used under this class.
c) Anionic surfactant: Sodium lauryl sulphate (SLS), Dioctyl sulphosuccinate are some examples of agents used under this class.
d) Bile salts: Sodium tauroglycocholate, Sodium deoxycholate are some of the examples of agents used under this class.
B. Solvents:
These agents act by possibly fluidizing the lipids or by swelling the polar pathway.
Ethanol, Methanol, dimethyl sulfoxide, Glycerol, Propylene glycol is some examples under this class.
4. Plasticizers [13],[14]
Plasticizers are the agents responsible for reducing the brittleness of the polymer film. They also provide flexibility or elasticity to the polymeric film. Above mentioned uses are observed at lesser concentration of plasticizer. At higher concentrations, it gives the polymeric film a sticky feel and makes it damp.
Ideal properties for agents to be used as plasticizer are as follows:
1. It should be easy to handle.
2. It should be easy to measure the contents accurately.
3. It should be non-reactive.
4. It should be non-toxic.
5. It should be pharmacologically inert.
6. It should not affect the stability of the drug.
7. It should not affect the stability of the final product.
8. It should not cause hypersensitivity reactions.
9. It should be easily available and inexpensive.
Polyethylene glycol, Glycerol, Propylene glycol, dibutyl phthalate is some of the examples of agents used as plasticizers in transdermal drug delivery systems.
5. Drug reservoir components [13],[15]
This mainly includes polymers either as a single polymer or in combination with other polymers in different concentration ratios depending on the density of matrix desired.
Ideal properties of drug reservoir components are as mentioned below:
1. It should be able to incorporate the required amount of drug to be formulated into final product.
2. It must not affect the release pattern of the drug throughout the usage period of the final product.
3. It must not alter or affect the physicochemical, biological or pharmacological properties of the drug.
4. Viscosity is an important parameter for semisolid transdermal drug delivery systems.
6. Backing laminates [7]
Backing laminates are used with an intention to provide support.
Ideal properties of backing laminates are as follows:
1. This should prevent the release of drug from the surface which is not in contact with the skin when the product is applied to the skin (i.e., from the top portion of the product).
2. They should be able to maintain a low rate of moisture or vapor transmission.
3. They must be compatible with drug and excipients of the formulation.
4. They must not only permit printing on their surface but should also be able to retain the print under various conditions of storage and usage.
5. They must be inexpensive and easily available.
6. Elasticity, flexibility and tensile strength are also an important parameter to be considered.
Metallic plastic laminate, Polyurethane(flexible), aluminium foil are some of the examples of backing laminates used in transdermal drug delivery systems.
7. Rate controlling membrane [7],[11]
Rate controlling membrane s regulate the rate at which drug is released from the product and presented to the skin for penetration.
This rate is dependent upon:
1. The pore size of the rate controlling membrane.
2. Molecular weight of the drug.
3. Molecular size of the drug.
4. Solubility of the drug under local conditions of product usage.
5. Thickness of the rate controlling membrane.
Ideal properties of the rate controlling membrane are as mentioned below:
1. Rate controlling membranes must regulate the release of drug at pre-determined rate with minute variations.
2. Membrane must maintain its integrity not only during the entire period of product usage but also till the shelf life of the product.
3. It must be nontoxic and non irritant to the skin.
4. It must not lead to hypersensitivity reactions.
5. It must be compatible with the drug and excipients used in the formulation.
Poly-2-hydroxyethyl methacrylate (PHEMA), chitosan is used as rate controlling membranes in transdermal drug delivery systems.
8. Adhesive layer[7],[4]
Adhesive layer fastens the transdrmal device on the surface of the skin ensuring its position on it under various mechanical stresses experienced during the period of usage. These are usually pressure sensitive.
Ideal properties of adhesives are as mentioned below:
1. Ability to stick with minimum pressure applied.
2. It should be removed without ant traces of adhesives.
3. It should not interfere with the release rate of the drug.
4. It should not affect the solubility of the drug.
5. It should not affect the sensitivity of the skin.
6. It should not affect the normal micro flora of the skin.
7. It should not alter the physicochemical and biological properties of the drug.
8. It should be nontoxic, non irritant and non allergenic to the skin.
9. It should be pharmacologically inert.
10. It should be compatible with the drug and excipients used in the formulation.
The three major classes of polymers used in transdermal drug delivery systems are:
1. Polyisobutylene type.
2. Acrylic type pressure.
3. Silicone type pressure.
9. Release liners[7],[13]
Release liners are protective layer which has to be removed before application of the product. These liners prevent the loss of drug during storage and transportation conditions. Silicon, Teflon, Polyesters are some examples of release liners.
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VARIOUS METHODS FOR PREPARATION TDDS
1. Circular Teflon mould method [7]
Polymers were dissolved in various ratios 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.
2. Mercury substrate method [7],[18]
Here, 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.
3. By using EVAC membranes method [11-13]
1% Corbopol reservoir gel, polyethylene (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 gel preparation. Drug is dissolved in propylene glycol; Corbopol 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 prevent leaking from device.
4. Aluminium backed adhesive film method [18]
TDDS 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. The drug is dissolved in chloroform and adhesive material will be added to the drug solution and dissolved. A custommade aluminium former is lined with aluminium foil and the ends blanked off with tightly fitting cork blocks.
5. By using free film method [7]
Free films of cellulose acetate are prepared by casting on mercury. 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. Polymer solution was poured in a glass ring which is placed over the mercury surface in a glass Petri-dish. The rate of evaporation of the solvent is controlled by placing an inverted funnel over the Petri-dish. The film formation is noted by observing the mercury surface after complete evaporation of the solvent. The dry film will be separated and in a desiccators until use. Free films of different thickness can be prepared by changing the volume of the polymer solution.
TYPES OF TRANSDERMAL PATCHES
1. Single layer drug in adhesive [16],[17]
Here, 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.
2. Multi -layer drug in adhesive [17]
This system is similar to the single layer but it contains an immediate drug release layer and other layer will be a controlled release along with the adhesive layer. The adhesive layer is responsible for the release of the drug. This patch also has a temporary liner-layer and a permanent backing layer.
3. Vapour patch [16]
Here, the role of adhesive layer not only serves to adhere to the various layers together but also serves to release vapour. The vapour patches are new and are commonly used for releasing of essential oils in decongestion. Various other types of vapor patches are also available in the markets which are used to improve the quality of sleep and reduce the cigarette smoking.
4. Reservoir system[18],[19]
Here, 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 either micro porous or non porous. In the drug reservoir compartment, the drug can be in the form of a solution, suspension or dispersed in a solid polymer matrix. Hypoallergenic adhesive polymer can be applied as outer surface polymeric membrane which is compatible with drug.
5. Matrix system [7],[18]
a. Drug-in-adhesive system:
Here, the drug reservoir is formed by dispersing the drug in an adhesive polymer and then spreading the medicated adhesive polymer by solvent casting or melting on an impervious backing layer. On the top of reservoir, unmediated adhesive polymer layers are applied for protection purpose.
b. Matrix-dispersion system:
Here, the drug is dispersed homogenously in a hydrophilic or lipophilic polymer matrix. This drug containing polymeric disc is fixed to an occlusive base plate in a compartment fabricated from a drug impermeable backing layer. Adhesive is spread along with the circumference to form a strip of adhesive rim.
6. Microreservoir system[7]
Here, the drug delivery system is a combination of reservoir and matrix-dispersion system. The 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 microscopic spheres of drug reservoir. This thermodynamically unstable dispersion is stabilized quickly by immediately cross-linking the polymer in situ by cross linking agents.
FACTORS AFFECTING TRANSDERMAL PERMEATION
1. Penetrate concentration [7],[19]
Increasing concentration of dissolved drug causes a proportional increase in flux. At concentration higher than the solubility, excess solid drug functions as a reservoir and helps to maintain a constant drug concentration for a long period of time.
2. Partition coefficient[7]
A lipid/water partition coefficient value of 1 or greater is required for optimal transdermal permeability. It may be altered by chemical modification without affecting the pharmacological activity of the drug.
3. pH conditions [14]
Applications of solutions whose pH values are either in high or low extremities can be destructive to the skin. With moderate pH values, the flux of ionizable drugs is affected by changes in pH that alter the ratio of charged and uncharged species and their transdermal permeability.
4. Release characteristics[7],[11]
Solubility of the drug in the vehicle affects the release rate. The mechanism of drug release depends on the following factors:
a. Whether the drug molecules are dissolved or suspended in the delivery systems.
b. The interfacial partition coefficient of the drug from the delivery system to the skin tissue.
c. pH of the vehicle
5. Composition of the drug delivery systems[19]
The composition of the drug delivery system which includes boundary layers, thickness, polymers and vehicles which not only affects the rate of drug release, but also the permeability of the stratum corneum by means of hydration, making with skin lipids, or other sorption promoting effects e.g., benzocaine permeation decreases with PEG of low molecular weight.
EVALUATION PARAMETERS
1. Interaction studies[18]
Excipients are an essential part of any formulation. No dosage form is possible to formulate with only drug. Interaction studies are performed to confirm the absence of any chemical reaction between drug and excipients of the formulation during various stages of manufacturing process. Interaction studies are performed by various analytical techniques like:
A. UV spectroscopy.
B. Thermal analysis.
C. FT-IR spectroscopy.
D. Chromatographic techniques.
2. Weight uniformity [7],[20]
The prepared patches are dried for 4 hours at 60?C before performing the test. A specific part of a definite dimension is cut from various parts of the patch and weighed on a digital balance. The average weight and standard deviation values are then calculated.
3. Thickness of the patch [18],[21]
The thickness of the drug loaded patch is determined at different points by using a digital micrometer. The average thickness and standard deviation are then calculated from individual values.
4. Percentage Moisture content[21]
The drug loaded patches are weighed individually and kept in a desiccator containing fused calcium chloride at room temperature for 24 hrs. After 24 hrs the films are reweighed. Determine the percentage moisture content from the below mentioned formula:
% moisture content = [Initial weight- Final weight/ Final weight] ×100.
5. Percentage Moisture uptake[18],[21]
The drug loaded patches are weighed and kept in a desiccator at room temperature for 24 hrs containing saturated solution of potassium chloride in order to maintain 84% RH. After 24 hrs the films are reweighed and the percentage moisture uptake is determined from the below mentioned formula:
% moisture uptake = [Final weight- Initial weight/ initial weight] ×100.
6. Folding endurance[7],[21]
A strip of specific dimension is cut evenly and repeatedly folded at the same place until it breaks. The number of times the film could be folded at the same place without breaking indicates the magnitude of folding endurance. Usually the test is repeated for 5 patches selected at random. The average value and standard deviation are then calculated.
7. Water vapour permeability (WVP) evaluation [7],[18]
Water vapour permeability is determined by 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 24hrs, W is the amount of vapour permeated through the patch expressed in gm/24hrs and A is the surface area of the exposure samples expressed in m2.
8. Uniformity of dosage unit test [22]
An accurately weighed portion of the patch is cut into small pieces and transferred to a volumetric flask. Contents of the flask are dissolved in a suitable solvent and sonicated for complete dissolution 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 0.2µm membrane filter and analyzed by suitable analytical technique (UV or HPLC).
9. Drug content[7],[18],[22]
A specified area of patch is to be dissolved in a suitable solvent in volumetric flask. The solution is then filtered through a filter medium and analyzed using suitable method (UV or HPLC technique).
10. Shear Adhesion test[23]
This test is to be performed for the measurement of the cohesive strength of adhesives. It dependent on 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 its 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.
11. Polariscope examination [7],[23]
This test is performed to examine the drug crystals from patch by using a polariscope. A specific surface area of the piece is to be kept on the object slide and observed for drug crystals to distinguish whether the drug is present in crystalline form or amorphous form.
12. Thumb tack test [7],[23]
It is a qualitative test to evaluate tack property determination of adhesive. The thumb is simply pressed on the adhesive and the relative tack property is detected.
13. Flatness test[23]
Three longitudinal strips are cut from each film from different portion like one from the center, other one from the left side, and another one from the right side. The length of each strip was measured and the variation in length because of non-uniformity in flatness was measured by determining percent constriction, with 0% constriction equivalent to 100% flatness. The average value and standard deviation are calculated.
14. Peel Adhesion test [24]
In this test, the force required to remove an adhesive coating form a test substrate is determined. Molecular weight of adhesive polymer, the type and amount of adhesives are the variables that determined the peel adhesion properties. A single tape is applied to a stainless steel plate or a backing membrane and then the tape is pulled from the substrate at 180º. The force required to remove the tape is measured.
15. Rolling ball tack test [7]
This test measures the softness of a polymer that relates to tack. 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 travelled by the ball along the adhesive provides the measurement of tack, which is expressed in inch.
16. Percentage Elongation break test [18]
The percentage elongation break is 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/ L2 × 100
Where, L1is the final length of each strip and L2 is the initial length of each strip.
17. Probe Tack test [24]
In this test, the tip of a clean probe with a defined surface roughness is brought into contact with adhesive. A bond is formed between probe and adhesive during this contact time. The subsequent removal of the probe mechanically breaks it. The probe is pulled away and force required to pull the probe away is determined.
18. Quick Stick (peel-tack) test[24]
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.
19. In vitro drug release studies [7],[18]
This test was performed using franz diffusion cell. The dissolution medium used was phosphate buffer (pH 7.4). Samples were withdrawn maintaining sink conditions and were evaluated for drug content using suitable analytical techniques.
20. Skin Irritation study[7],[18],[25]
This test is performed on animals and human volunteers. Relevant approvals and permissions form various regulatory boards are a must to proceed with the test. Pre-treatment of the animal to remove the hair is necessary. Various dehairing techniques can be employed. The patch is to be removed after 24 hr and the skin is to be observed and classified into 5 grades on the basis of the severity of skin injury.
21. Stability studies[7],[25]
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.
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NEW APPROACHES IN TDDS:
1. Iontophoresis [13],[15]
It involves application of current (few mill-amperes) to the drug reservoir with a charged electrode. Permeability of the stratum corneum is increased in the presence of an electric current. Pilocarpine delivery is an example to induce sweat in the diagnostic of cystic fibrosis and Iontophoretic delivery of lidocaine is considered as rapid approach for anesthesia.
2. Reverse Iontophoresis (RI) [7],[14]
Symmetrical nature of iontophoresis has led to its application as a non-invasive method of extracting endogenous substances known as reverse iontophoresis.
3. Electroporation [26]
The electrical pulses forms small pores in the stratum corneum through which transportation of drug occurs. For safe and painless administration, the electrical pulses are introduced by closely spaced electrodes to reserve the electric field within the stratum corneum. High voltages (100 V) and short treatment durations (milliseconds) are frequently employed.
4. Photomechanical Waves [27]
Photomechanical waves make the stratum cornea highly permeable to drug substance through a possible permeabilisation mechanism due to development of transient channels.
5. Medicated Tattoos (Med-Tats) [7]
Medicated - Tattoos are modification of temporary tattoo which contains an active drug substance. This is useful in the administration of drug in those children who are not able to take traditional dosage forms. There is no predetermined duration of therapy for Med–Tats; instead, the manufacturer provides a color chart that can be compared to the color of the patient’s tattoo to determine when the tattoo should be removed. This visual comparison, which relies on the dyes incorporated into the patch, introduces a significant amount of interpatient variability.
6. Microneedle-based Devices [7],[12]
It was first described in 1976 and consisted of a drug reservoir and a plurality of projections (microneedles 50 to 100 mm long) extending from the reservoir, which penetrated the stratum corneum and epidermis to deliver the drug.
7. Skin Abrasion [12],[13]
This involves removal or disruption of the upper layers of the skin to facilitate the permeation of topically applied medicaments. Some of these devices are based on techniques employed by dermatologists for superficial skin resurfacing which are used in the treatment of acne, scars, hyperpigmentaion and other skin blemishes.
8. Laser Radiation [11],[27]
It involves direct and controlled exposure of a laser to the skin that results in the ablation of the stratum corneum without significantly damaging the underlying epidermis. Removal of the stratum corneum using this method has been shown to enhance the delivery of lipophilic and hydrophilic drugs.
9. Ultrasound (sonophoresis and phonophoresis) [11],[13]
This involves use of ultrasonic energy to enhance the transdermal delivery of solutes either simultaneously or via pre-treatment. This system uses low frequency ultrasound (55 kHz) for an average duration of 15 seconds to enhance skin permeability.
10. Needle-less Injection[7],[27]
This involves firing of liquid or solid particles at supersonic speeds through the outer layers of the skin using a suitable energy source. The mechanism involves forcing compressed gas (helium) through the nozzle, with the resultant drug particles entrained within the jet flow reportedly traveling at sufficient velocity for skin penetration.
CONCLUSION
TDDS is very helpful to the patients suffering from the dreadful diseases, where the localization of the specific target becomes difficult during therapy. This review article provides valuable information regarding the transdermal patches and its evaluation process details as a ready reference for the research scientists who are involved in TDDS. TDDS have great potentials, being able to use for both hydrophobic and hydrophilic active substance into promising deliverable drugs. The application of TDDS has increased because of high end technology and devices.
REFERENCES
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