Transdermal drug delivery an emerging approach for antipsychotics

Transdermal drug delivery system is one of the leading technology which gives extensive bene its compared to other dosage forms. In the case of drugs having a irst-pass metabolism problem, small doses of drugs can be delivered. Oral drug delivery is associated with several problems like pain interrelated with the use of injections,needles, and the researchers mainly focus on the development of the transdermal route. The aim is to provide a rationale for improvement of the transdermal system of antipsychotics by highlighting the antipsychotic formulation and safely delivering medications across the skin.The present review emphasis on the latest advances in a transdermal delivery system which acts as a platform for effective transdermal delivery of antipsychotic. By using this technique, the pharmacotherapy of patients who have psychosis can be improved. There are numeral physical methods, and the skin penetration enhancement techniques have been developed that helps in delivering drugs through the skin.This technique helps to alter the barrier properties of skin and improves the penetration of the drug.It majorly highlights the possible role of microneedle in the transdermal system and acts as a different carrier in delivering several therapeutic agents effectively. This article summarizes thenovel transdermal delivery approaches, advantages, and the choice of antipsychotropic drugs.


INTRODUCTION
Transdermal drug delivery system (TDDS) is a trouble-free technique for delivering drugs systemically by applying a medication onto unbroken & well skin. The penetration of the drug through stratum corneum and passes through deeper epidermis and dermis without increasing the drug level in the dermal layer (Alkilani et al., 2015). Transdermal patchwork in a pretty simple way. Patches are a drug in the adhesive (DIA) system in which drug is distributed in pressure-sensitive adhesive (PSA) matrix. The transdermal patch includes constituents likePSA, the release liner, backing membrane, and few excipients (Nandgude and Ganapathy, 2017). The transdermal system was irst introduced in the mid-1990s, and this technology made great interest for researchers and pharmaceutical companies. This review article describes various components of the transdermal patch and its application, advantages disadvantages, and few recent advancements in this ield. Innovations in novel technology occur at a positive rate, which leads to a productive and pulsating area of innovation for research and product development. Numerous physical, chemical, biochemical strategies are used to disrupt the stratum corneum to enhance transdermal drug delivery, with physical procedures like thermal ablation, electrically assisted meth-ods, e.g. electroporation, iontophoresis (ITP) and currently developed strategies like microneedles. Microneedle is a sub-millimetre device that creates a microchannel (Earle and Subramanyam, 2014). It is a minimally invasive method that evades the stratum corneum without exciting the dermal nerves or bleeding. Small molecules to nanoparticles can be transported through the skin by microneedle. The present review mainly focuses on the use and development of microneedle, its type, and application, which signi icantly enhances drug delivery through the transdermal route. All across the world, the transdermal patch market has risen to 2 billion dollars. In 1979 the irst FDA approved the transdermal system for motion sickness was "SCOP-Transderm" (Mehta, 2004).

Structure of skin
The human skin is the external covering of the body and largest organ of the integumentary system, having a surface area of 1.7 m 2 comprising of 15-16 % of total body form. The major function of the skin is a defensive barrier between the drug and external environment against UV radiations, allergens, microorganisms, and chemicals. Skin is divided into three major regions: (1) Epidermis-the outmost layer comprises stratum corneum (2) Hypodermisthe innermost layer (3) Dermis-the middle layer. The stratum corneum is around 10-20 micrometer thick and it acts as anobstruction for drug penetration, it allows only lipophilic molecules to diffuse through the skin. The removal of stratum corneum and viable epidermis leads to a rise in drug delivery (Patole et al., 2013;Alkilani et al., 2015).

Principles of Transdermal Permeation
The drug enters the bloodstream through the skin through the process of diffusion. Earlierthe skin was considered asan impervious protective barrier, but a future investigation was accepted which showed the effectiveness of skin as a route for systemic administration. Penetration through viable epidermis and sorption by stratum corneum (Tiwari, 2013).

Components of TDDS
The transdermal system is made up of Drugs, Polymer matrix, Penetration enhancers, Adhesives, Backing laminates, Release linear. Figure 1 depicts the essential components of Tdds (Prabhakar and Sreekanth, 2013;Sudam and Suresh, 2016).

Drug
There is direct contact of Drug Solution with release liner. The drug parameter considered is as below.      3. A daily dose of the drug must be a few mg/day.

Polymer Matrix
Polymer Matrix acts as a backbone for the transdermal drug delivery system. Change in polymer composition leads to a change in the release rate from TDS. Hence polymer selection is important in designing a variety of membrane perme-ation (Hejase et al., 2011;Nandgude and Ganapathy, 2017).
Basic criteria for polymer selection are: 1. The polymer must be non-toxic.
2. The polymer must be stable.
3. The polymer should be an inert drug carrier.
4. It must be biocompatible with the skin surface.
5. The polymer should be non-toxic and nonantagonistic to the host.
6. The polymer must be in-expensive

Penetration Enhancer
Penetration enhancer is a combination that supports the permeability of the skin by modifying the skin as a barrier. When penetration enhancer is mixed with the formulation, it improves the A) Diffusivity B) Solubility of Drug through the skin. Penetration enhancers inally allow the drug to penetrate from the viable tissue and move in systemic circulations.

Pathways of Drug Penetration
Transportation of penetrant through skin barrier by three signi icant pathways such as intercellular penetrationfrom the stratum corneum, transappendageal penetration through hair follicles and sweat and sebaceous gland, the transcellular /intracellular permeation takes place through the stratum corneum (Ramesh and Velraj, 2018).
Ideal Penetration enhancers must have the following properties 1. It must be non-irritant, non-toxic, and nonallergic 2. No pharmacological activity within the body 3. Penetration enhancers must work unifacial.

Adhesive
Adhesive it acts as a vital component by forming the contact between the delivery system and with skin. Pressure-sensitive adhesive is placed outside of the device or at the posterior of the device (Prabhakar and Sreekanth, 2013).
Adhesion is the net effect of three phenomena mainly, 1. Peel: It has resistance against the cracking of the adhesive bond 2. Tack: Polymer can adhere to the substrate with small contact pressure 3. Creep: There is tacky relaxation of the adhesive bond upon shear Adhesive Material and its Ideal Characters 1. It must be able to remove it easily.
2. It must have good contact with the skin surface.
3. It must be non-irritant 4. Should not produce washable residue on the skin 5. The drug must have physical & chemical compatibility (Nandgude and Ganapathy, 2017).

Antipsychotic
"Psychosis" disorder is severe mental disorders that affect abnormal thinking and disturbs brain function. Psychiatric illness such as schizophrenia leads to a condition of psychosis. Signi icant symptoms include: (Gardner, 2005) Hallucinations, delusions, talking illogically. The patient isn't aware of his or her behaviour. Antipsychotics are the medications that are used to alter mental conditions like psychosis. It is also called major tranquillizers or neuroleptics (Cipollina, 1992). Based on the extrapyramidal effect, the drugs are classi ied as typical and atypical antipsychotics, which are used to treat bipolar disorder like (mixed episodes and acute mania) (Tandon, 2011). The atypical antipsychotic is favoured as it has a more favourable adverse effect pro ile and has a low charge for causing transformation from mania to depression. The use of antipsychotic drugs achieves the blocking of the D2 receptor. Antipsychotic drugs are useful in monitoring symptoms of acute schizophrenia (Cummings, 1992;Nussbaum and Ellis, 2003;Björkelund et al., 2006). The list of marketed TDDS products are mentioned in Table 1 (Kumar and Philip, 2007;Saroha et al., 2011).

Novel Enhancement Techniques for Skin Permeation
Various technology has been used for modi ication in barrier properties of stratum corneum, and this is divided into passive/chemical or active/physical methods.
Chemical penetration enhancer is the most widely used passive approach. Various mechanism of action for penetration enhancers are as follows: 1. The stratum corneum lipid bilayers luidity is increased.

Interruption or extraction of intercellular lipids
3. Contact with intercellular proteins 4. The thermodynamic activity of drug increases which leads to an increase in stratum corneum hydration The most widely used penetration enhancers are alcohol, azone, essential oils, sulphoxides, urea, fatty acids, and water. Penetration enhancers are associated with limitations such as reduced ef icacy and safety (Alkilani et al., 2015).
A practical method for skin penetration includes: Through these approaches, a wide range of drugs can be delivered across the skin.The active method can provide a wide range of medications which overwhelms lag time. Figure 2 depicts the approaches for enhancing drug transport across the skin (Alkilani et al., 2015).
Few active methods involve the use of the following methods,

Ultrasound devices
Ultrasound is known as an oscillating sound pressure wave which has a wide application in the ield of chemistry, biology, physics, and engineering. By applying a Frequency of 20 kHz-16 MHz, there is a transport of drugs across the skin (Han and Das, 2015). Diverse categories and types of drugs can be effectively delivered by applying ultrasound (Schoellhammer et al., 2014). Mechanism of ultrasound which affects tissue and cells includes cavitation effect and thermal effect. The mechanism involves the oscillation of cavitation bubbles in the ultrasound ield (Seah and Teo, 2018).

Physical Enhancement Approaches
It includes major two types a) Indirect physical method and b) Direct physical method

Indirect Physical Method
For enhancement, Several new approaches are involved in the application of electrical (Iontophoresis, sonophoresis, electroporation, and innovative methods such as magnetic energy and laser energy for commercial purposes) (Benson et al., 2019).

Iontophoresis
In Iontophoresis, a milliampere of current is applied to a speci ic area of skin. The mechanism involves the use of an electrode, which is in contact with the medication which needs to be administered. By potential gradient, the charged drugs are passed from the skin and into the body. For the enhancement of a wide range of drugs, Iontophoresis has been widely studied (Benson et al., 2019). In September 2015 the security patch was introduced, but its sales were ceased in June 2016 as it showed burns at the application site. Three Iontophoretic delivery systems developed to include a) Phoresor b) Lidosite c) E-trans. Lidosite is used for fast dermal anaesthesia, and it delivers Lidocaine which is the irst approved commercial iontophoretic patch.
Iontophoresis has a wide application in diagnosis and therapeutic use. This process can enhance the permeation of topically applied therapeutic agents. Figure 3 depicts the representation of an iontophoresis patch.
Micro iontophoresis is a system that is used to study cellular function, by using a small size capillary probe, that releases particular quantities of active substances (Nanda et al., 2006).

Electroporation
In this approach, the high intensity of the electric pulse is applied which leads to the creation of aqueous openings in the lipid bilayer of stratum corneum and permits diffusion of drug diagonally to the skin (Alkilani et al., 2015). A voltage of 50-500V is used, which increases the passage across the skin. The electrical parameters and physicochemical properties of drugs lead to an increase in the transport of drugs. This expertise has been used to enhance skin penetrability of different molecules with different sizes (i.e. proteins, peptides, oligonucleotides). The principle of electroporation is shown in Figure 4 (Nanda et al., 2006).

Sonophoresis
Sonophoresis involves a blend of ultrasound treatment and topical drug treatment to reach therapeutic drug concentration at speci ic places of the skin. The system which uses ultrasound to increase the absorption of topical medication onto the skin is called as sonophoresis. A low-frequency pressure wave of not more than 100 kHz is applied, because of this, the molecules get to penetrate through the skin easily (Park et al., 2014;Seah and Teo, 2018). Sonophoresis is used in the treatment of muscle soreness and tendonitis. The mechanism involved in this technique is a)Cavitation (generation and oscillation of gas bubbles) b)Thermal Effect (Increase in Temperature) Sonophoretically enhanced transdermal drug delivery system has a wide application in gene therapy and tissue engineering (Stanekzai et al., 2019). Sonophoresis transdermal drug transport can be used in the ield of biotechnology and genetic engineering (Bhatt and Aqil, 2010).

Magnetophoresis
In this technique, the magnetic ield is applied, which acts as an energetic force to upsurge the dispersion of diamagnetic solute across the skin (Kumar and Philip, 2007).

Velocity based Devices
Devices that are dependent on velocity includes the powder or liquid jet injection, which uses a highvelocity jet having velocity 100 to 200m/s for puncturing the skin, and by using power sources such as compressed gas or spring, it delivers the drug. Liquid jet injectors are of two types: 1. The single-dose jet injector (disposable cartridge jet injectors)

Multi-use-nozzle jet injectors (MUNJIs)
A jet injector is a useful device that helps to deliver drugs in an electronically controlled manner and is a needle-free device which results in enhanced uniformity and reduces pain in the patient.
Liquid jet injector pushes the liquid from the nozzle having a diameter of 50 to 350um, which is smaller than the hypodermic needles (800um). Delivery of drugs to different layers of the skin can be achieved by using a jet of different ori ice diameter and velocity the drug is delivered. The signi icant bene it of this method is secure and safe needle disposable without any accidental needle injury. Therefore multi-nozzle jet injectors are limited to provide only multi-dose drugs to an individual. E.g., Tjet device delivers somatropin, i.e. (human growth hormone) (Kumar and Philip, 2007).
The advantage of a powder jet injector over liquid jet injector is it can deliver reliable drugs or vaccines to the skin. Eg-DNA vaccination has a particle size between 0.5um to 3 um (Arora et al., 2008).

Thermal Approach
In the thermal ablation approach, systemic delivery of drugs across the skin by warming the surface of the skin, which exhausts the stratum corneum at speci ic sites of heating only without affecting the deeper tissue. By using ohmicmicroheaters and radio-frequency, ablation skin heating can be achieved (Bhatt and Aqil, 2010).
Methods used for thermal ablation includes-"laser and radiofrequency".

Laser Thermal Ablation
Laser ablation is used for the treatment of dermatological situations like pigmented skin. The mechanism involved in laser thermal ablation is the removal of stratum corneum without damaging the deeper tissue. Thus it improves the supply of lipophilic and hydrophilic drugs into the skin surface (Baron, 2003). By the installation of light energy, the laser removes the stratum corneum leading to loss of water and the development of microchannels in the skin (Saravanakumar, 2015).

Radiofrequency Thermal Ablation
Radiofrequency thermal ablation is a technique that is used to reduce pain. The microscopic pathway in stratum corneum is produced by applying a highfrequency irregular current of (~100 kHz) by which the drug gets penetrated.
This method permits the transdermal delivery of an extensive range of hydrophilic drugs and macromolecules (Bala, 2014).

Biochemical Enhancer
Proteins/peptides are used instead of chemical as a chemical enhancer. E.g., Natural pore-forming peptide, i.e., magainin. When a surfactant and chemical enhancer is used in combination, magainin, it acts as an effective enhancer. Figure 5 depicts the different classes of chemical enhancers (Pathan and Setty, 2009;Das and Ahmed, 2017).

Mechanical approach
Some of the innovative approaches are used to overcome the dif iculties and novel methods like MN and tape stripping methods are useful. These area few advanced methods that have a wide application in the transdermal drug delivery system (Prabhakar and Sreekanth, 2013;Alkilani et al., 2015).

Tape Stripping
In this system repeated applications of an adhesive tape that eradicates the skin layer, SC. The amount of stratum corneum removed by a single adhesive factors such as the patient's age, the thickness of stratum corneum and the extent of lipid should be considered. The pH and transepidermal water loss are theskin parametersthatneed to be measured (Akhtar et al., 2020).
It is a technique that can be used in ecological research -dermatopharma for selectively removing the skin (Lademann et al., 2009).

Microneedle
It is the most recently developed drug delivery system which is similar to the conventional needle. Still, the difference is they are fabricated in a micron size range of 1-100 micron in length and of a diameter of 1 micron Akhtar (2014). MN array is a good alternative for hypodermic and subcutaneous needles. Other than pain-free delivery it has various advantages such as MN does not cause bleeding, it eliminates the dosing unevenness of small molecules, potential for self-administration, it avoids needle stick injuries and ease of MN waste disposal. MN approach provides tremendous ampli ication potential for a preferred immune response (Giannos, 2014). Figure 6 depicts the image of the mechanism of action of a microneedle array Marketed Micro needle products are Intanzia and Micronjet which are prepared for metals and silicon respectively. Intanza was the irst in luenza vaccine that targets the dermis. Sano i Pasteur MSD ltd developed the intanza. During the designing as well as fabrication of MN, the shape and geometry are very much critical.  (Arora et al., 2008)

Solid microneedle
It creates microholes across the skin, which increases the permeability of the drug formulations. After insertion of the microneedle, there is the formation of micro-channels that helps in the transport of drugs to viable epidermis. Solid MN consist of the "Poke and patch" approach. Metals, silicon, and polymers can be used for the fabrication of solid MN (Benson et al., 2019).

Coated microneedle
It is used for the fast dissolution of coated drugs into the skin. It is a one-step application process, but the dosage is limited to the amount of coating.
Coated MN has a wide application in the ield of vaccines. Coated MN consist of the "Coat and poke" approach (Gill and Prausnitz, 2007).

Dissolvable microneedle
Materials used in Dissolvable MN it forms a sharp estimate with the payload dissolved or suspended within, allowing it to poke into and then dissolved within the skin to release the payload.Dissolvable MN involves encapsulation of the drug inside the biodegradable polymeric microneedles. Polymers used in dissolvable MN are PLA, PGA, PLGA, PVP, Polycarbonate (Ito et al., 2012).

Hollow microneedle
Hollow MN is used to rupture the skin surface and in-turn discharge the lique ied drug (Arora et al., 2008). Hollow MN contains a deep bore at the centre of the needle. It works by the mechanism of diffusion or active infusion of the preparation over the needle bores. The approach involved in hollow MN is the "Poke and low" approach. By diffusion process, it carries the drug continuously into the body. It can also be used to remove the luid from the body for analysis purposes. The representation of four different MN is shown in Figure 7 (Martanto et al., 2006).

Ruggedness
To resist the inclusion force deprived of being fractured.

Penetration
It is Essential to pierce the medication to deepness in the tissues.

Cellular delivery
MN has a wide application in cellular delivery.
The Membrane impermeable molecules can be delivered into the cells by this method.

Systemic delivery
The use of MN overcomes the restrictions of injections.

Biopharmaceuticals
Microneedles can deliver insulin, heparin, growth hormones and human growth hormone.

Immunobiologicals
Microneedles have an advantage over other methods due to the absence of pain. E.g., in luenza vaccine, hepatitis B vaccine, etc.

Cosmetics
The main stream dermatological products are imparted through the microneedle tools and are used for non-surgical action. eg: used in the management of Ageing (wrinkles). Patole et al. (2013).

Microneedle Geometry characterization
The tip radius, base, and thickness of MN are determined by scanning electron microscopy. These values measure interfacial interaction between the skin and the needle.

Safety margin
The proportion between the force essential for penetrating the stratum corneum and the power where the microneedles brakes are called a margin of safety. For biomedical application microneedle array of a ratio, less than 1(<1) can be used.

Diffusion Test
For evaluating the penetration of model drug, Franz diffusion cell is used.

Trans Epidermal Water Loss (TEWL)
When water is passed from dermis through the epidermis, and it gets evaporate from the skin surface, it is known as TEWL. It is used to characterize the skin barrier function. The principal involved in this process is diffusion and evaporation. The probes are positioned in the wheel clamp beyond the application site. At several times interims earlier and later the application of microneedle the estimates were measured for about three minutes.In humans, the TEWL is about 300-400mL/day.

Biological Safety Test
From microneedle, the chemicals were pulled out by dipping them in physiological saline solution at 37ºC for 72 hours.the extract obtained was applied on shaved intact human skin. If dermal irritation is absent, then it is proved that the biological safety of microneedle (Mathur et al., 2010;Earle and Subramanyam, 2014).

Future of the transdermal system
TDDS is best for delivering oral and injected drugs. Because of low skin permeability,various types of drugs do not pass across the skin. Iontophoresis, as well as Sonophoresis, are two recently developed methods for improving the skin penetration. Iontophoresis involves the use of electrical current along the dual electrodes on the skin surface. Sonophoresis works by the mechanism of ultrasonic energy,which transfers drugs of high molecular weight over the skin. Most advanced, as well as favourable technology is microneedle enhanced drug delivery. The most interesting & new concept, i.e. microneedle, has a generous value in the future (Caffarel-Salvador and Donnelly, 2016).

Global TDDS Market
The world wide TDDS (percutaneous) has a market value of USD 5400.2 million till 2017 and is predicted to reach a CAGR of 4.6% in the coming years.The international transdermal market is estimated to touch 81.4 billion USD by 2024 as per the report of grand view research. The advancement includes third-generation TDDS includes ultrasound, Iontophoresis, and microneedle Gowthaman et al. (2015). In 2015, in North America, the overall TDDS market had increased by more than 50.0 %. The list of antipsychotic drugs in TDDS is mentioned in Table 2 (Isaac and Holvey, 2012;Ita, 2017;Abruzzo et al., 2019). Radio frequency, Electroporation, Iontophoresis, Microporation, Thermal, Ultrasound, Mechanical Arrays, Others CONCLUSION TDDS is one of the leading sectors in the ield of the pharmaceutical industry. Ever since 1981, the TDDS is used for delivering drugs safely. A lot of development is done in the area of transdermal patches. Nowadays, many researchers are working on innovative medicines to be given via TDDS, and it offers excellent therapeutic response. It is expected that technological development in TDDS leads to improvement in the prevention of disease, diagnosis, and upgrading of the life of the patient.In this review, several new TDDS approach needs to be established to overcome the limitation of the conventional method. In this review, we advise using innovative methods of the microneedle. A wide range of materials can be utilized for fabrication. Microneedle has extensive use in the ield of medicine for drug delivery, diagnosis, and vaccination. Other practices like Iontophoresis and electroporation are combined with microneedle to boost penetration into the skin. Due to exponential development in investment and attention in the MN approach have a wide application. This article offers valuable data regarding the transdermal drug delivery system and different novel approaches in TDDS.