Abstract

The goal of a transdermal drug delivery system (TDDS) which falls under the category of controlled drug delivery, is to deliver the medication through the skin at a predetermined and regulated rate. Longer therapeutic impact, fewer side effects, increased bioavailability, better patient compliance, and simple medication therapy termination are just a few of its many benefits. For the majority of molecules, the stratum corneum is thought to be the rate-limiting barrier in transdermal penetration. The appendageal, transcellular, and intercellular pathways are the three primary ways that drugs can enter the body. When administering medication by this method, a number of parameters need to be taken into account, including skin age, condition, physicochemical characteristics, and ambient conditions. The polymer matrix, membrane, drug, penetration enhancers, pressure-sensitive adhesives, backing laminates, and release are the fundamental elements of TDDS.

Keywords

Introduction

 

 

 

 

restricted because perspiration moves against the permeant's diffusion route. The lipid-rich sebum produced by sebaceous glands may act as a barrier to hydrophilic medications.
Shortly after the vehicle is applied, it has been proposed that the shunt route is usually the predominate pathway.^[17] Transepithelial pathways become increasingly significant after steady-state diffusion is established.^[18] It has been suggested that the appendageal pathway may be significant for large polar compounds and ions, even though its contribution to flow is typically thought to be minimal.^[19]

4.2 The Transcellular Path

Corneocytes allow drugs to penetrate the skin through the transcellular pathway. Drugs that are hydrophilic can pass through the aqueous environment created by corneal cells, which include extremely hydrophilic keratin. The lipid envelope that envelops the cells binds them to the interstitial lipids. Multiple lipid bilayers separate keratinized skin cells; each corneocyte is thought to have up to 20 of these lamellae.^[20] As a result, several partitioning and diffusion phases are needed for a drug's transcellular diffusion pathway. The permeant must first partition into the surrounding lipid envelope and then into and out of the several lipid bilayers that divide corneocytes after diffusing through and partitioning into the comparatively watery corneocytes.^[21] Whether the transcellular pathway is the predominant route adopted will be significantly influenced by the physicochemical characteristics of the permeant. The relative capacity to divide in and out of each skin phase is crucial, in particular. However, during steady-state flux, the transcellular pathway is believed to be the main conduit for extremely hydrophilic medicines.^[22]

4.3 Paracellular route

The most typical approach for drugs molecules to enter cells is through the paracellular route. The medication stays in lipid moeity and surrounds keratin in this pathway, making it easier for lipid-soluble drugs to do so than proteins.^[23]

5.  Kinetics Of Transdermal Permeation ^[24]

Skin permeation kinetics is important for the successful development of the transdermal systems. Transdermal permeation of a drug involves the following steps,

• Sorption by stratum corneum
• Penetration of drug through viable epidermis
• Uptake of the drug in the dermal papillary layer

The rate of permeation across the skin is given by, eqⁿ 1

        

                   dQdt

= P_S (C_d – C_r)          ……….1

 

Where, Ps is the overall permeability constant of the skin tissue to the penetrant

Cd is concentration of skin penetrant in the donor compartment (e.g., on the surface of stratum corneum)

Cr is concentration in the receptor compartment (e.g., body)

                    P_{s = KsDsshs}

                ………...2

 

Where,

Ks is the partition coefficient for the interfacial partitioning of the penetrant molecule from a solution medium onto the stratum corneum

 Dss apparent diffusivity of the penetrant molecule. hs 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 Eq.1 it is clear that a constant rate of drug permeation can be obtained only when i.e., the drug concentration at the surface of the stratum corneum (Cd) is greater than the drug concentration in the body (Cr) then Eq.1

 becomes, eqⁿ 3

                    dQdt

 = P_sC_d           ……..3

 

And the rate of skin permeation 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 i.e. either constant or greater than the rate of skin uptake Ra.

.i.e. Since Rr >> 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

 .i.e. Cd>>Cs. Therefore a maximum rate of skin permeation is obtained and is given by the equation, 4

                   ( dQdt )

_m = P_SCs        …….4

 

 From the above equation it can be seen that the maximum rate of skin permeation depends upon the skin permeability coefficient Ps and equilibrium solubility in the stratum corneum Cs. Thus skin permeation appears to be stratum corneum limited The membrane limited flux (J) under steady state condition is described by equation, 5

                     J = DCKo/wh

 

Where,

J is amount of drug passing through membrane system per unit area per unit time.

D is diffusion coefficient of drug within the membrane.

C is concentration gradient across the membrane.

K is the membrane / vehicle partition coefficient h is the membrane thickness.

6.  Types Of TDDS Patch

6.1 Reservoir system

The drug is encased in an impermeable backing laminate and a rate-regulating microporous or nonporous membrane in reservoir systems (figure 3). The drug is suspended in a viscous liquid medium and evenly distributed within a solid polymer matrix to form a paste.
The abrasion rate, permeability, diffusion, and membrane thickness all affect the drug's release rate. The reservoir system's release rate is a zero order process. The impermeable metallic backing serves as support for the entire system.^[25,26]

 

 

 

 

 

 

 

 

7.  Basic Components Of TDDS ^[32-34]

1. Polymer matrix / Drug reservoir
2. Drug Permeation enhancers
3. Pressure sensitive adhesive (PSA)
4. Backing laminates
5. Release liner and other excipients like plasticizers and solvents

7.1 Polymer matrix / Drug reservoir

The fundamental building blocks of TDDS are polymers, which regulate the drug's release from the apparatus. Drug dispersion in a liquid or solid state synthetic polymer basis can create a polymer matrix. The polymers used in TDDS should be chemically and biologically compatible with the medication and other system elements including PSAs and penetration enhancers. They should also be safe and distribute a drug consistently and effectively for the duration of the product's stated shelf life. Businesses in the transdermal delivery space focus on a small number of specific polymeric technologies. For instance, Searle Pharmacia focuses on silicon rubber, while Alza Corporation mostly works with microporous polypropylene or ethylene vinyl acetate (EVA) copolymers. Similarly, Sigma employs ethyl cellulose for the isosorbide dinitrate matrix while Colorcon, UK, uses HPMC for matrix preparation for propranolol transdermal administration.

The polymers used in TDDS fall into the following categories: Natural Polymers: e.g. cellulose derivatives, zein, gelatin, shellac, waxes, gums, natural rubber and chitosan etc.

Synthetic Elastomers: e.g. polybutadiene, hydrin rubber, polyisobutylene, silicon rubber, nitrile, acrylonitrile, neoprene, butylrubber etc.

Synthetic Polymers: e.g. polyvinyl alcohol, polyvinylchloride, polyethylene, polypropylene, polyurea, polyacrylate, polyamide, polyvinylpyrrolidone, polymethylmethacrylate etc. As matrix builders for TDDS, polymers such as cross-linked polyethylene glycol, eudragits, ethyl cellulose, polyvinylpyrrolidone, and hydroxypropyl methylcellulose are employed. As rate-controlling membranes, other polymers such as polyurethane, silicon rubber, and EVA are employed.

7.2 Drug

For drugs with the right pharmacology and physical chemistry, the transdermal route is a very alluring choice. Drugs with a limited therapeutic window, high first pass metabolism, or short half lives that result in non-compliance from frequent doses can benefit greatly from transdermal patches. The primary prerequisite for transdermal drug delivery (TDDS) is that the medication has the ideal combination of biological and physicochemical characteristics. The best drug candidates for passive adhesive transdermal patches are generally agreed to be non-ionic, have a low molecular weight (less than 500 Daltons), be potent (dose in mg per day), have a low melting point (less than 200°C), be sufficiently soluble in water and oil (log P in the range of 1-3), and be non-ionic. The medications that are currently available for transdermal administration are listed in Table 1. Furthermore, medications such as selegiline for depression, methylphenidate for attention deficit hyperactivity disorder, rotigotine for Parkinson's disease, and rivastigmine for Alzheimer's and Parkinson's dementia have recently been licensed as TDDS.

7.3 Permeation Enhancers

The three routes of polar, non-polar, and polar/non-polar drug penetration via the skin are proposed. One of these routes is changed by the enhancers. The key to changing the polar route is to induce solvent swelling or a change in protein structure. Modifying the lipid structure's stiffness and fluidizing the crystalline channel—which significantly boosts diffusion—are the keys to changing the nonpolar pathway. The fatty acid enhancers make the lipid layer of the stratum corneum more fluid.

Certain enhancers (binary vehicles) change the multilaminate pathway for penetrants, thereby acting on both polar and nonpolar pathways. Enhancers can dissolve skin lipids or denaturize skin proteins to improve medication diffusivity in the stratum corneum (SC). The kind of enhancer used has a big influence on how the product is developed and designed. The capacity of the medicine to permeate the skin in sufficient amounts to have the intended therapeutic effect is essential for the effectiveness of dermatological drug products designed for systemic drug administration, such as transdermal. The techniques used to alter the SC's barrier characteristics in order to improve drug penetration (and absorption) via the skin fall into two categories:

(1) chemical enhancement methods

(2) physical enhancement methods

7.3.1 Chemical Enhancers

Chemicals that promote the penetration of topically applied drugs are commonly referred to as accelerants, absorption promoters, or penetration enhancers. Chemical enhancers act by

• Increasing the drug permeability through the skin by causing reversible damage to the SC.
• Increasing (and optimizing) thermodynamic activity of the drug when functioning as co solvent.
• Increasing the partition coefficient of the drug to promote its release from the vehicle into the skin.
• Conditioning the SC to promote drug diffusion.
•  Promoting penetration and establish drug reservoir in the SC.

7.3.2 Physical enhancers

Examples of physical enhancement techniques that have been utilized to improve the percutaneous penetration (and absorption) of different therapeutic substances are iontophoresis and ultra sound (sometimes referred to as phonophoresis or sonophoresis).

7.4 Pressure sensitive adhesives

A PSA is a substance that aids in preserving close contact between the skin's surface and the transdermal system. It should be aggressively and persistently sticky, exert a strong holding force, and adhere with no more finger pressure than is applied. It should also be able to be removed without leaving any residue from the smooth surface. TDDSs frequently use silicon-based adhesives, polyacrylates, and polyisobutylene. The drug's composition and patch design are two of the many considerations that go into choosing an adhesive. An inadvertent interaction between the adhesive and the drug and penetration enhancer in matrix systems with a peripheral adhesive shouldn't result in instability for either the drug, the adhesive, or the penetration enhancer. When a face adhesive is incorporated into reservoir systems, the diffusing drug must not affect the adhesive. The choice of drug-in-adhesive matrix systems will be determined by how quickly the drug and penetration enhancer diffuse through the adhesive. PSA should ideally not change medication release and be compatible with both biology and chemistry.

7.5 Backing Laminate

The most crucial factor to take into account while creating a backing layer is the material's chemical resistance. Compatibility of the excipients should also be taken into account because extended contact between the excipients and the backing layer may result in the additions leaking out of the layer or in the diffusion of the drug, excipients, or penetration enhancer through the layer. On the other hand, if chemical resistance is overemphasized, it could result in stiffness and high occlusiveness to moisture vapor and air, which could cause patches to lift and irritate the skin over time. The backing with the lowest modulus or high flexibility, good oxygen transmission, and a high moisture vapor transmission rate will be the most comfortable. Vinyl, polyethylene, and polyester films are a few examples of backing materials.

7.6 Release Liner

The protective liner that covers the patch during storage is taken off and discarded right away before the patch is applied to the skin. As a result, it is thought of as a component of the main packing material rather than the drug delivery dosage form. The liner must, however, meet certain standards for chemical inertness and permeability to the drug, penetration enhancer, and water because it comes into close contact with the delivery system. A release liner is usually made comprised of a silicon or teflon release coating layer and a base layer that can be either occlusive (like paper fabric) or non-occlusive (like polyethylene or polyvinyl chloride). Metallized laminates and polyester foil are additional materials utilized for TDDS release liners.

7.7 Other excipients

 Various solvents such as chloroform, methanol, acetone, isopropanol and dichloromethane are used to prepare drug reservoir. In addition plasticizers such as dibutylpthalate, triethyl citrate, polyethylene glycol and propylene glycol are added to provide plasticity to the transdermal patch.

8.  Enhancement Of Transdermal Delivery By Equipment

Drugs and biomolecules are known to be more permeable through the skin when exposed to external stressors such as electrical, mechanical, or physical stimuli, as opposed to topical drug administration.^[35] With the correct equipment, active transdermal delivery, or TDDS, is a method that has been shown to deliver medications into the skin quickly and reliably. Additionally, this enhanced TDDS mode (Fig. 2) can speed up the therapeutic efficacy of medications administered.^[36–38]

8.1 Iontophoresis

Iontophoresis has been shown to enhance skin penetration and accelerate the release of several drugs with poor absorption/permeation profiles by promoting the passage of ions across the membrane when a small external potential difference (less than 0.5 mA/cm²) is applied. This technique has been utilized to transport ionic or non-ionic drugs in vivo by creating an electrochemical potential gradient.^[39] The effectiveness of iontophoresis is dependent on the medication formulation, the type of applied electrical cycle, and the polarity, valency, and mobility of the medicinal molecule. In particular, iontophoresis's dependence on current lessens the dependence of drug absorption on biological factors, in contrast to most other drug delivery methods.^[40] This approach may also include electronic reminders for patients to modify their medicine, if they so choose, in order to increase patient compliance.^[41,42]

8.2 Sonophoresis

Transdermal medication administration can be enhanced by the required range of ultrasonic frequencies produced by an ultrasound device.^[43,44] Because it creates an aqueous channel in the disturbed bilayer by cavitation, low-frequency ultrasound is more effective in facilitating drug flow.^[45] The medicine in issue is mixed with a specific coupler, such as a gel or cream, which disturbs the layers of the skin using ultrasonic vibrations, creating an aqueous channel via which the drug can be administered. Typically, passageways created by applying ultrasonic waves with energy between 20 kHz and 16 MHz are used to transport medications. Furthermore, ultrasound creates a thermal impact and increases the skin's local temperature, which further promotes drug absorption. This method has been used to give a variety of medications, including mannitol and high molecular weight (MW) pharmaceuticals like insulin, regardless of their solubility, dissociation and ionization constants, and electrical properties (including hydrophilicity). The exact mechanism of medication penetration with this technique is still unclear, and problems with device availability, maximizing exposure time and treatment cycles for administration, and adverse side effects including burns persist.

8.3 Electroporation

This method applies high voltage electric pulses, ranging from 5 to 500V, to the skin for short exposure times (~ms), creating microscopic pores in the SC that improve permeability and facilitate drug diffusion.^[46,47] Electric pulses are introduced using closely spaced electrodes to provide medications safely and painlessly. This procedure, which involves permeabilizing the skin, is extremely safe and painless. It has been used to successfully deliver high MW drugs like oligonucleotides, antiangiogenic peptides, and the negatively charged anticoagulant heparin, as well as low MW drugs like doxorubicin, mannitol, or calcein. Low delivery loads, substantial cellular disruption that can occasionally lead to cell death, drug destruction caused by heat, and denaturation of proteins and other biomacromolecular therapies are some of the disadvantages of this strategy.

8.4 Microneedles

The microneedle drug delivery system is a novel drug delivery technique that uses a needle to deliver drugs to the circulatory system.^[48] Research in this field is still ongoing, and it is one of the most popular methods for transdermal drug delivery. This method involves puncturing the outermost layer of the skin with micron-sized needles, which allows medications to permeate into the epidermal layer. By delivering drugs directly to the blood capillary region for active absorption, these minuscule, thin needles can avoid pain.^[49] The broad goal of microneedle research is represented by the various methods that scientists have tried to employ for the proper optimization and geometric measures needed for the successful insertion of microneedles into human skin. Numerous studies have been conducted on the creation of microneedle systems, taking into account the target for use, drug kind and dosage, and objective.^[50] Currently, photolithography and laser-mediated methods can be used to create the microneedle. Metal or polymer microneedles are made using laser-mediated fabrication processes. A laser is used to cut or ablate a flat metal or polymer surface to create the three-dimensional structure of a microneedle.^[51,52] The process of intricately creating microneedles, or photolithography, has the benefit of producing needles in a variety of shapes and materials. This technique is mostly used to create silicon or dissolving/hydrogel microneedles by etching photoresist to create an inverse mold based on the microneedle structure.^[53] Additionally, two photon polymerization^[56],microstereolithography^[55] ,and 3D printing^[54] are being researched for preparing different microneedle systems.
Preparation of microneedles can take many forms: solid microneedles that only establish a physical route for drug absorption; drug-coated microneedles that carry drugs coated on their surfaces as they penetrate the skin; dissolving microneedles composed of drug formulations that dissolve in the body; naturally delivered melting needles that store drugs in hollow needles prior to administration (e.g., a specific type of injection); and microneedle patches combined with different types of patches.^[57–61]

8.5 Needleless jet injectors

There are commercially available devices that give protein and peptides without causing pain by rapidly delivering the powders or liquids into the skin. Unlike typical injections, this delivery method offers a needleless alternative. They come in two different forms: liquids and particles. The Vitajet (Bioject), Biojector (Bioject), and Medi-Jector systems, together with their related variations [Biojector—Cool. click and SeroJet (Serono); Medi-Jector—Zomajet (Ferring)], are a few examples of jet injections of proteins in liquid form. Furthermore, ganirelix, recombinant human growth hormone (hGH), and insulin can all be administered needleless with these products. The pharmacokinetic characteristics are identical to those seen when needle injections are used. This system's advantage is that it causes less pain than traditional needles, which increases patient compliance, particularly for kids with diabetes.^[62]

8.6 Magnetophoresis

The use of a magnetic field to improve medication penetration through biological barriers is known as magnetophoresis.^[63] Benzoic acid, salbutamol sulfate, and terbu taline sulfate are among the medications whose transdermal penetration may be aided by the static magnetic field. The intriguing concept of using magnetism or microchip-based devices to distribute medications in a regulated, pulsatile mode was covered by Langer (2000).^[64] The application of magnetite-incorporated particle systems in imaging and medication delivery has been the subject of several investigations. An externally applied magnetic field has been proven to drive they stemically delivered magnetoliposomes or nanoparticles to the target region.^[65] As effective delivery vehicles, these materials have been used more and more, opening up possibilities for usage as MRI agents, cancer treatment mediators for hyperthermia, and in targeted therapies.^[66] A biocompatible polymer must be used as the coating agent for para and superparamagnetic particles in the polymeric matrix for this purpose. Magnetophoretic patch systems distribute medications more quickly than thermomagnetic patch systems, according to in vivo trials conducted on pig skin.

8.7 Photomechanical waves

Pressure waves, which are produced by powerful laser radiation, have the ability to permeabilize both the SC and the cell membrane. The device is renowned for its ability to precisely control the depth of ablated skin and for clearly defining the ablated range.^[67] Since these are essentially compression waves, cavitation-induced biological impacts are not included. Their amplitude is in the hundreds of atmospheres (bar), and their duration is between a few microseconds and nanoseconds. In contrast to ultrasound, the pressure waves have distinct interactions with cells and tissue.^[68] Lee and colleagues (1999) came to the conclusion that photomechanical waves are solely responsible for straining the horny layer and improving drug distribution when a medication solution is applied to the skin and covered with a black polystyrene target. The laser parameters (wavelength, pulse duration, and fluency) as well as the optical and mechanical characteristics of the target material determine the PW's components (peak pressure, rising time, and duration). The coupling coefficient indicates the efficiency of PW production, or the transformation of light energy into mechanical energy. The coupling coefficient can be used to compute the peak pressure. Drugs administered through the epidermis have the ability to enter the blood vessels and have a systemic effect. Thus, pressure waves can be used to deliver insulin and the human ?-aminolevulinic acid (ALA) allergen quickly.^[69]

8.8 Electron beam irradiation

Radiation has been shown to be an effective method for creating polymer matrices that can immobilize a variety of medications at both room temperature and below.^[70] Nuclear track microporous membranes, which are employed as medication release rate regulating membranes for TTS, were created using a unique alpha particle irradiation process. One of the special characteristics of radiation polymerization is that it involves the final matrix without any leftover initiator. The procedure is carried out in broad sterilization of the product, so radiation polymerization is chosen over thermochemical technique. Radiation polymerization is more energy efficient since its activation energy is only one-third that of thermochemical processes. In order to evaluate the solid state stability of the drug to irradiation, Kotiyan and colleagues created a transdermal system of isosorbide dinitrate (ISDN) using this method. The result was improved skin penetration kinetics when compared to a transdermal matrix system of ISDN that is sold internationally.^[71]

9.  Evaluation Parameters ^[72-78]

9.1 Interaction studies:

 In practically every pharmacological dose form, excipients are essential ingredients. Among other things, a formulation's stability is determined by how well the drug and excipients work together. To create a stable product, the drug and the excipients must work well together. Therefore, it is essential to identify any potential physical or chemical interactions as they may impact the drug's stability and bioavailability. Compatibility studies are crucial to formulation development if the excipients are novel and haven't been used in formulations with the active ingredient. By comparing their physicochemical characteristics, such as assay, melting endotherms, distinctive wave numbers, absorption maxima, etc., interaction studies are frequently conducted in thermal analysis, FT-IR, UV, and chromatographic procedures.

9.2 Thickness of the patch:

To confirm the thickness of the prepared patch, the thickness of the drug-loaded patch is measured at several spots using a digital micrometer. The average thickness and standard deviation are then calculated.

9.3 Weight uniformity:

 The prepared patches are to be dried at 60°c for 4hrs 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.

9.4 Folding endurance:

 A strip of specific are 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.

9.5 Percentage Moisture content:

 The prepared films are to be weighed individually and to be kept in a desiccator Containing fused calcium chloride at room temperature for 24 hrs. After 24 hrs 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.

9.7 Water vapour permeability (WVP) evaluation:

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 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.

9.8 Drug content:

 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 analyse the drug contain with the suitable method (UV or HPLC technique). Each value represents average of three different samples.

9.9 Uniformity of dosage unit test:

 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 m membrane filter and analysed by suitable analytical technique (UV or HPLC) and the drug content per piece will be calculated.

9.10 Polariscope examination:

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.

9.11 Shear Adhesion test: 

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 crosslinking 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.

9.12 Peel Adhesion test:

Peel adhesion is the term used in this test to describe the force needed to remove an adhesive covering from a test substrate. The variables that influenced the peel adhesion qualities were the adhesive polymer's molecular weight and the kind and quantity of additives. The force needed to remove a single piece of tape is measured after it has been attached to a stainless steel plate or any preferred backing membrane. The tape is then pulled from the substrate at a 180º angle. The force needed to remove an adhesive covering from a test substrate is known as peel adhesion. The molecular weight of the sticky polymer, the kind and quantity of additives, and the composition of the polymer all influence peel adhesion characteristics. The force needed to pull a single coated tape placed to a substrate at an 1800 angle is measured in order to test it. For transdermal devices, "adhesive failure" is indicated by the absence of residue on the substrate. Remains on the substrate show "cohesive failure," which denotes a coating's lack of cohesive strength. Adhesive should allow the device to make sufficient contact with the skin and not cause any harm when removed.

9.13 Thumb tack test:

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.

9.14 Flatness test:

Three longitudinal strips are to be cut from each film at different portion like one from he 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.

9.15 Percentage Elongation break test:

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 / L2] ×100

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

9.16 Rolling ball tack test:

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.

9.17 Quick Stick (peel-tack) test:

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.

9.18 Probe Tack test:

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.

9.19 In vitro drug release studies:

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 h and analyzed by UV spectrophotometer or HPLC. The experiment is to be performed in triplicate and the mean value can be calculated.

9.20 In vitro skin permeation studies:

An in vitro permeation study can be carried out by using diffusion cell. Full thickness abdominal skin of male Wistar rats of weighing 200 to 250g. 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 analysed 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 cm 2) vs. time in hours and permeability coefficients were deduced by dividing the flux by the initial drug load (mg cm 2).

9.21 Skin Irritation study:

 Skin irritation and sensitization testing can be performed on healthy rabbits (average weight 1.2 to 1.5 kg). The dorsal surface (50cm²) 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 hr and the skin is to be observed and classified into 5 grades on the basis of the severity of skin injury.

9.22 Stability studies:

 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 analyse suitably for the drug content.

10.  Challenges And Opportunities of Transdermal Drug Delivery System ^[79]

Transdermal delivery of drugs is both intriguing and problematic. There are several transdermal delivery techniques available on the market. However, the transdermal market only offers a restricted selection of medications. Advancements in transdermal delivery require overcoming problems such as drug penetration and skin irritation (Vol. 1 No. 10, 2012). New strategies for improving skin penetration and reducing irritation could expand the transdermal market for hydrophilic chemicals, macromolecules, and conventional medicines for new therapeutic applications. Transdermal medication delivery has a promising future, as evidenced by ongoing clinical trials across multiple illnesses. Drug delivery through the skin presents both an appealing and daunting research opportunity. Transdermal delivery of drugs, including hydrophobic small molecules and macromolecules, is becoming more common because to technological advancements. Hydrophilic drugs and transdermal systems offer significant advantages over other methods of medication administration. Transdermal delivery offers patients a pain-free and easy way to self-administer medications. This method avoids the need for frequent dosage, as well as the peaks and troughs in plasma levels caused by oral dosing and injections. It also allows for easy delivery of drugs with short half-lives.  This improves patient compliance, particularly for long-term treatments like chronic pain and smoking cessation. Transdermal administration of weakly bioavailable drugs avoids hepatic first-pass metabolism and the GI tract, providing an additional benefit. Eliminating the first pass impact provides for safer drug administration in hepato-compromised patients, reducing unwanted effects. Transdermal systems offer lower monthly costs than other therapies due to their ability to supply drugs for 1-7 days. Transdermal delivery offers many dosing options, including on-demand or variable-rate delivery, which enhances the benefits of traditional patch dosage forms. Transdermal products are well accepted among patients, as evidenced by their growing market. The transdermal delivery of drugs market was valued $12.7 billion in 2005 and is projected to reach $32 billion in 2015. Transdermal delivery systems (TDS) were first launched to the US market in the late 1970s, however the practice of delivering drugs through transdermal means dates back much further. Previous research suggests that mustard plasters can relieve chest congestion and belladonna plasters can provide pain relief. Mustard plasters were both homemade and commercially accessible. They were created by grinding mustard seeds and mixing them with water to create a paste. This paste was then used as a dispersion method. When applied to the skin, enzymes triggered by body heat produce allyl isothiocyanate, the active component. Passive diffusion via the skin transports the drug's active component, which is the basis for transdermal drug delivery. Over time, transdermal patches for nicotine, methylphenidate, testosterone, and lidocaine have been developed. Prausnitz et al. characterized the many generations of TDSs generated over time. The initial generation of molecules was primarily tiny, lipophilic, and uncharged, allowing for therapeutic delivery through passive diffusion. This generation is responsible for the majority of TDS on the market today. Advancements in science and engineering have led to the employment of chemical enhancers, ultrasound, and iontophoresis to deliver medication molecules that cannot diffuse naturally. These transdermal devices are part of the second generation, targeting reversible disruption of the skin's stratum corneum or using an additional driving force to deliver drugs. In 2012, an iontophoretic delivery device was created and launched to distribute lidocaine, a charged chemical. Microneedles and electroporation are being used in developing a third generation of delivery devices for macromolecules. The third generation of methods targets the stratum corneum rather than modifying the drug molecule itself. Recent reviews cover many elements of transdermal delivery, including generational classification, market trends, and the use of nanotechnology. Patent reviews on transdermal delivery formulations and procedures have been published. The purpose of this article is to provide an updated review of transdermal products available in the US market and in clinical trials.

11.  Advance Development In TDD ^[79]

Adhesive technology is the main method for passive transdermal drug administration. Formulation research focuses on adhesives and excipients. Adhesive research aims to enhance skin adherence, improve medicine stability and solubility, reduce lag time, and speed up delivery. Customizing adhesive chemistry allows transdermal formulators to optimize patch performance, as a one-size-fits-all adhesive cannot support all drug and formulation chemistries. Over the past 10-15 years, research has focused on developing transdermal technologies that use mechanical energy to increase drug flux across the skin. This involves either altering the skin barrier (primarily the stratum corneum) or increasing the energy of drug molecules. Active transdermal technologies include iontophoresis, electroporation, sonophoresis, and thermal energy. Iontophoresis uses low voltage electrical current to drive drugs through the skin, while electroporation creates transient aqueous pores. Sonophoresis uses low frequency ultrasonic energy to disrupt the stratum corneum. Magnetophoresis, a technique that uses magnetic energy to accelerate medication flux over the skin, has been researched.

CONCLUSION:

This article provide an valuable information regarding the transdermal drug delivery systems and its evaluation process details as a ready reference for the research scientist who are involved in TDDS. The foregoing shows that TDDS have great potentials, being able to use for both hydrophobic and hydrophilic active substance into promising deliverable drugs. To optimize this drug delivery system, greater understanding of the different mechanisms of biological interactions, and polymer are required. TDDS a realistic practical application as the next generation of drug delivery system.

REFERENCES

1. Loyd V. Allen Jr, Nicholas G. Popovich, Howard C. Ansel. Pharmaceutical dosage forms and drug delivery systems, 8th Edition., Wolter Kluwer Publishers, New Delhi, 2005 pp. 298-299.
2. Valecha V., Mathur P., Syan N., Verma S., Various Penetration Enhancements Technique in Transdermal Drug Delivery, International Journal of Pharmacy and Technology, 3(2), 2011, 2373-2401.
3. Keleb E., Sharma R.K., Mosa E.B., Aljahvi A.Z., Transdermal Drug Delivery System-Design and Evaluation, International Journal of Advances in Pharmaceutical Sciences, 1, 2010, 201-211.
4. Economidou, S. N., Lamprou, D. A. & Douroumis, D. (2018). 3D print ing applications for transdermal drug delivery. International Journal of Pharmaceutics, 544(2), 415–424.
5. Erd?, F., Hashimoto, N., Karvaly, G., Nakamichi, N., & Kato, Y. (2016). Critical evaluation and methodological positioning of the transder mal microdialysis technique. A review. Official Journal of Controlled Release Society, 233, 147–161.
6. Patel A, Visht S, Sharma PK. Transdermal Drug Delivery System: Next Generation Patches. J Drug Discov Dev 1, 43-65.
7. Kumar JA, Pullakandam N, Prabu SL, Gopal V. Transdermal drug delivery System: An overview. Int J Pharma Sci Rev Res 2010; 3(2):49-53.
8. Jain NK. Advances in controlled and novel drug delivery. 1st Ed. CBS Publishers and distributors, New Delhi, 2001, 108-110.
9. Yamamoto T, Katakabe K, Akiyoshi K, Kan K and Asano T. Topical Application of Glibenclamide Lowers Blood Glucose Levels in Rats. Diabetes Res. Clin. Pract. 1990; 8: 19-22.
10. Singh H, Sharma R, Joshi M, et al. Transmucosal delivery of docetaxel by mucoadhesive polymeric nanofibers. Artif Cells Nanomed Biotechnology. 2014;12-18.
11. Latheeshjlal L, Phanitejaswini P, Soujanya Y, Swapna U, Sarika V, Moulika G, Transdermal Drug Delivery Systems: An Overview, Int J Pharm Tech Res 2011; 3(4):2140-2148. 9.
12. Chien YW, Novel drug delivery systems, drugs and the pharmaceutical sciences, Vol.50, Marcel Dekkar, New York, 1992, 797.
13. Banker GS, Rhodes CT. Modern pharmaceutics, third edition, New York, Marcel Dekkar Inc, 1990.
14. Guy RH. Current status and future prospects of transdermal drug delivery. Pharm Res 1996; 13:1765 1769.
15. Benson HAE. Transdermal Drug Delivery: Penetration Enhancement Techniques, Current Drug Delivery 2005; 2:23-33.
16. Guy RH, Hadgraft J, Bucks DA, Transdermal drug delivery and cutaneous metabolism, Xonobiotica 1987; 7:325-343.
17. Scheuplein RJ, Blank IH. Permeability of the skin. Physiol Rev 1971; 51: 702-47.
18. Scheuplein RJ. Mechanism of percutaneous absorption. II. Transient diffusion and the relative importance of various routes of skin pene tration. J Invest Dermatol 1967; 48: 79-88.
19. Dokka S, Cooper SR, Kelly S, Hardee GE, Karras JG. Dermal deliv ery of topically applied oligonucleotides via follicular transport in mouse skin. J Invest Dermatol 2005; 124: 971-5.
20. Wertz PW, Swartzendruber DC, Abraham W, Madison KC, Down ing DT. Essential fatty acids and epidermal integrity. Arch Dermatol 1987; 123: 1381-4.
21. Hadgraft J, Guy R, editors. Transdermal Drug Delivery. Develop mental Issues and Research Initiatives. New York: Marcel Dekker; 1989.
22. Williams AC. Transdermal and topical drug delivery. London: Phar maceutical Press; 2003.
23. Parnami, Nupur, Tarun Garg, Goutam Rath, and Amit K. Goyal. 2013. “Development and Characterization of Nanocarriers for Topical Treatment of Psoriasis by Using Combination Therapy.” Artificial Cells, Nanomedicine, and Biotechnology 42 (6): 406–12.
24. Yadav V. Transdermal drug delivery system: review. Int. J Pharm Sci. Res. 2012;3(2):376-382.
25. Sharma N., Agarwal G., Rana A.C., Bhat Z.A., Kumar D., A Review: Transdermal Drug Delivery System: A Tool for Novel Drug Delivery System, International Journal of Drug Development & Research, 3(3),2011, 70-84.
26.  Joseph R.R., Vincent H.L.L., Controlled Drug Delivery, Fundamentals and Applications, 2nd Edition, Revised and Expanded, Informa Healthcare, Replika Press Pvt. Ltd.,1987, 523-552.
27. Wokovich A.M., Prodduturi, Doub W.H., Hussain A.H., Buhse L.F., Transdermal Drug Delivery System (TDDS) Adhesion as a Critical Safety, Efficacy and Quality Attribute, European Journal of Pharma and Biopharm, 64, 2006, 1-8.
28. Tyle P., Drug Delivery Device, 3rd Edition, New York and Basal, Marcel Dekker, 2003, 417-449.
29. Arunachalam A., Karthikeyan M., Viney D.K., Pratap. M., Sethuraman S., Ashutoshkumar S., Manidipa S., Transdermal Drug Delivery System: A Review, Current Pharma Research, 1(1), 2010, 70-81.
30. Lalita K.L., Grampurohit N.D., Gaikwad D.D., Gadhave M.V., Jadhav S.L., Transdermal Patches: A Review, International Journal of Pharmaceutical Research and Development, 2011, 4(3), 2012, 96-103.
31. Walter M., Transdermal Therapeutic System (TTS) With Fentanyl as Active Ingredient, European Patent, EP 1418951, (2004).
32. Jain, N. K., Controlled and Novel Drug Delivery, CBS Publishers, and Distributors, 2002, 107.
33. Chien, YW, Novel drug delivery systems, Drugs and the Pharmaceutical Sciences, Vol.50, Marcel Dekker, New York, NY;1992;797
34. Jain.N.K, Controlled and novel drug delivery, first edition, CBS publishers and distributors, New Delhi.1997.
35. Benson HA, Grice JE, Mohammed Y, Namjoshi S, Roberts MS. Topical and transdermal drug delivery: from simple potions to smart technologies. Curr Drug Deliv. 2019;16(5):444–60.
36. Lee HJ, Song CY, Baik SM, Kim DY, Hyeon TG, Kim DH. Device-assisted transdermal drug delivery. Adv Drug Deliv Rev. 2018;127:35–45.
37. Bird D, Ravindra NM. Transdermal drug delivery and patches- an overview. Med Devices Sens. 2020;3(6):e10069.
38. Hanbali OA, Khan HS, Sarfraz M, Arafat M, Ijaz S, Hameed A. Transdermal patches: design and current approaches to painless drug delivery. Acta Pharma. 2019;69(2):197–215.
39. Wang Y, Zeng L, Song W, Liu J. Influencing factors and drug application of iontophoresis in transdermal drug delivery: an overview of recent progress. Drug Deliv Transl Res. 2021.
40. Dhal S, Pal K, Giri S. Transdermal delivery of gold nanoparticles by a soybean oil-based oleogel under iontophoresis. ACS Appl Bio Mater. 2020; 3(10):7029–39.
41. Moarefian M, Davalos RV, Tafti DK, Acheniec LE, Jones CN. Modeling iontophoretic drug delivery in a microfluidic device. Lab Chip. 2020;20(18): 3310–21.
42. Byrne JD, Yeh JJ, DeSimone JM. Use of iontophoresis for the treatment of cancer. J Control Release. 2018;284:144–51.
43. Park J, Lee H, Lim GS, Kim N, Kim D, Kim YC. Enhanced transdermal drug delivery by sonophoresis and simultaneous application of sonophoresis and iontophoresis. AAPS PharmSciTech. 2019;20(3):96.
44. Seah BC, Teo BM. Recent advances in ultrasound-based transdermal drug delivery. Int J Nanomedicine. 2018;13:7749–63.
45. Nguyen HX, Banga AK. Electrically and ultrasonically enhanced transdermal delivery of methotrexate. Pharmaceutics. 2018;10(3):117.
46. Charoo NA, Rahman Z, Repka MA, Murthy SN. Electroporation: An avenue for transdermal drug delivery. Curr Drug Deliv. 2010;7(2):125–36.
47. Chen X, Zhu L, Li R, Pang L, Zhu S, Ma J, et al. Electroporation-enhanced transdermal drug delivery: effects of logP, pKa, solubility and penetration time. Eur J Pharm Sci. 2020;151:105410.
48.  Agrawal S, Gandhi SN, Gurgar P, Saraswathy N. Microneedles: An advancement to transdermal drug delivery system approach. J Appl Pharm Sci. 2020;10(3):149–59.
49. Zhao Z, Chen Y, Shi Y. Microneedles: a potential strategy in transdermal delivery and application in the management of psoriasis. RSC Adv. 2020; 10(24):14040–9.
50. Jung JH, Jin SG. Microneedle for transdermal drug delivery: current trends and fabrication. J Pharm Investig. 2021
51. Shakya AK, Ingrole RSJ, Joshi G, Uddin MJ, Anvari S, Davis CM, et al. Microneedles coated with peanut allergen enable desensitization of peanut sensitized mice. J Control Release. 2019;314:38–47.
52. 45. Lim J, Tahk D, Yu J, Min DH, Jeon NL. Design rules for a tunable merged-tip microneedle. Microsyst Nanoeng. 2018;4(1):1–10.
53. Dardano P, Caliò A, Palma VD, Bevilacqua MF, Matteo AD, Stefano LD. A photolithographic approach to polymeric microneedles array fabrication. Materials. 2015;8(12):8661–73.
54. Han D, Morde RS, Mariani S, Mattina AAL, Vignali E, Yang C, et al. 4D printing of a bioinspired microneedle array with backward-facing barbs for enhanced tissue adhesion. Adv Funct Mater. 2020;30(11):1909197.
55. Xiao Z, Li X, Zhang P, Wang Y. Research of polymeric microneedles for transdermal drug delivery. Progress Chem. 2017;29(12):1518.
56. Balmert SC, Carey CD, Falo GD, Sethi SK, Erdos G, Korkmaz E, et al. Dissolving undercut microneedle arrays for multicomponent cutaneous vaccination. J Control Release. 2020;317:336–46 .
57. Kim HM, Lim YY, An JH, Kim MN, Kim BJ. Transdermal drug delivery using disk microneedle rollers in a hairless rat model. Int J Dermatol. 2012;51(7): 859–63.
58. Li K, YooKH, ByunHJ, LimYY, KimMN, HongHK, et al. The microneedle roller is an effective device for enhancing transdermal drug delivery. Int J Dermatol. 2012;51(9):1137–9.
59. Bariya SH, Gohel MC, Mehta TA, Sharma OP. Microneedles: an emerging transdermal drug delivery system. J Pharm Pharmacol. 2012;64(1):11–29.
60. Lee YS, Kang TG, Cho HR, Lee GJ, Park OK, Kim SY, et al. Localized delivery of Theranostic nanoparticles and high-energy photons using microneedles on-bioelectronics. Adv Mater. 2021;33(24):2100425.
61. Du H, Liu P, Zhu J, Li Y, Zhang L, Zzhu J, et al. Hyaluronic acid-based dissolving microneedle patch loaded with methotrexate for improved treatment of psoriasis. ACS Appl Mater Interfaces. 2019;11(46):435;88–98.
62. H.A. Benson, S. Namjoshi, Proteins and peptides: strategies for delivery to and across the skin, J. Pharm. Sci. 97 (2008) 3591–3610.
63. S.N. Murthy, S.M. Sammeta, C. Bowers, Magnetophoresis for enhancing transdermal drug delivery: mechanistic studies and patch design, J. Control. Release 148 (2010) 197–203.
64. S.N. Murthy, Magnetophoresis: an approach to enhance transdermal drug diffusion, Pharmazie 54 (1999) 377–379.
65. M. Arruebo, R. Fernández-Pacheco, M.R. Ibarra, J. Santamaría, Magnetic nanoparticles for drug delivery, Nano Today 2 (2007) 22–32.
66. S.F. Medeiros, A.M. Santos, H. Fessi, A. Elaissari, Stimuli-responsive magnetic particles for biomedical applications, Int. J. Pharm. 403 (2011) 139–161.
67. M. Ogura, S. Sato, K. Nakanishi, M. Uenoyama, T. Kiyozumi, D. Saitoh, T. Ikeda, H. Ashida, M. Obara, In vivo targeted gene transfer in skin by the use of laser-induced stress waves, Lasers Surg. Med. 34 (2004) 242–248.
68. A.G. Doukas, N. Kollias, Transdermal drug delivery with a pressure wave, Adv. Drug Deliv. Rev. 56 (2004) 559–579.
69. J.R. Nethercott, Practical problems in the use of patch testing in the evaluation of patients with contact dermatitis, Curr. Probl. Dermatol. 2 (1990) 97–123.
70. M. Yoshida, M. Kumakura, I. Kaetsu, Drug entrapment for controlled release in radiation-polymerized beads, J. Pharm. Sci. 68 (1979) 628–631.
71. P.N. Kotiyan, P.R. Vavia, Y.K. Bhardwaj, S. Sabarwal, A.B. Majali, Electron beam ir radiation: a novel technology for the development of transdermal system of isosorbide dinitrate, Int. J. Pharm. 270 (2004) 47–54.
72.  Crawford R.R and Esmerian O.K. Effect of plasticizers on some physical properties of cellulose acetate phthalate films. J. Pharm. Sci. 1997;60: 312- 314.
73.  Shaila L, Pandey S and Udupa N. Design and evaluation of matrix type membrane controlled Transdermal drug delivery system of nicotin suitable for use in smoking cessation. Indian Journ. Pharm. Sci. 2006;68: 179-18.
74.  Aarti N, Louk A.R.M.P, Russsel.O.P and Richard H.G. Mechanism of oleic acid induced skin permeation enhancement in vivo in humans. Jour. control. Release 1995; 37: 299-306.
75.  Wade A and Weller P.J. Handbook of pharmaceutical Excipients. Washington, DC: American Pharmaceutical Publishing Association 1994; 362-366.
76. Lec S.T, Yac S.H, Kim S.W and Berner B. One way membrane for Transdermal drug delivery systems / system optimization. Int. J Pharm. 1991; 77: 231 - 237.
77. Vyas S.P and Khar R.K. Targetted and controlled Drug Delivery Novel carrier system1st Ed., CBS Publishers and distributors, New Delhi, 2002; 411-447.
78.  Singh J, Tripathi K.T and SakiaT.R. Effect of penetration enhancers on the invitro transport of ephedrine through rate skin and human epidermis from matrix based Transdermal formulations. Drug Dev.Ind. Pharm. 1993; 19: 1623-1628.
79. Bhowmik D, Duraivel S, Kumar KS. Recent trends in challenges and opportunities in transdermal drug delivery system. The Pharma Innovation. 2012 Dec 1;1(10)