INTRODUCTION:

Often referred to as "patches," transdermal drug delivery systems (TDDS) are dosage forms intended to distribute a therapeutic dosage of medication across a patient's skin. It is necessary to take into account the skin's entire morphological, biophysical, and physicochemical characteristics in order to provide medicinal substances through the skin for systemic effects. By improving patient compliance and eliminating first pass metabolism, transdermal delivery offers a significant advantage over injectables and oral routes, respectively.

In addition to allowing for continuous, controlled medication administration, transdermal distribution also prevents pulsed entrance into the systemic circulation, which frequently results in unwanted side effects. Consequently, a variety of innovative medication delivery methods, including transdermal, transmucosal, and controlled medicines with brief biological half-live and release mechanisms².

Limiting hepatic first-pass metabolism, improving therapeutic efficacy, and maintaining a constant medication plasma level are some significant benefits of transdermal drug administration. In 1979, the FDA approved Transderm-SCOP, the first transdermal device, to reduce travel-related nausea and vomiting, especially when traveling by sea. Measurable drug levels in the blood, detectable drug and metabolite excretion in the urine, and the patient's clinical reaction to the prescribed medication therapy can all be used as indicators of percutaneous drug absorption.

Now a day many drugs are administered orally, but they are observed not more effective as desired so to upgrade such character TDDS was created. Drug delivery administered by the skin and attain a systemic effect of drug is called as transdermal drug delivery system. These are kind of dosage form which includes drug transport to reasonable epidermis and potentially dermal tissue of the skin locally therapeutic effect. While an exceptionally signiﬁcant division of the drug is transported in systemic blood circulation. A transdermal dermal patch is characterized as a medicated adhesive patch which is set over the skin to deliver a particular dose of medication by the skin with a foreordained rate of release³.

Advantages^3,4:

· By improving bioavailability, the drug avoids first-pass metabolism by avoiding hepatic and pre-systemic metabolism.

· Boost adherence from patients

· It doesn't affect the stomach and intestinal fluids.

· Self-management is feasible.

· Preventing medication levels from fluctuating.

· Preserve the powerful drug's plasma concentration.

· Drug distribution can be readily stopped in cases of toxicity.

· Enhance therapeutic efficacy.

· Capacity to distribute the medication more precisely to a certain location.

· It is simple to stop therapy at any time.

Physiology of skin:

The average adult's skin is about 2m 2 in size and has three morphologically distinct layers: the basal layer, the spiny layer, the stratum granulosum, and the uppermost stratum corneum. The skin is made up of highly cornified (dead) cells that are embedded in a continuous matrix of blood that circulates throughout the body. The epidermis, the topmost layer of skin, features thin membrane sheets. Ceramides, cholesterol, and free fatty acids make up the special composition of these extracellular membranes. It is known that there are, on average, 200–250 sweat ducts and 10–70 hair follicles per square centimeter of human skin⁴.

The biggest organ in the body, the skin serves as an essential barrier to protect the body from a variety of dangers and environmental influences. Because of its huge surface area—roughly 1.7 square meters in a typical person—it can efficiently protect the body against toxins, allergies, ultraviolet (UV) radiation, bacteria, and water loss. For general health and wellbeing to be maintained, this protective role is essential.

Furthermore, through exposure to sunlight, the skin contributes to the regulation of body temperature, sensation, and vitamin D production. Maintaining the skin's health and supporting its functions requires proper care⁵.

Fundamental Elements of TDDS:

A. Polymer matrix:

One essential and vital component of the transdermal drug delivery method is polymer. Numerous polymeric material types have been employed to provide rate-controlled medication distribution. The drug release mechanism is determined by the physicochemical properties of the drug and the polymer used in the device's fabrication. A polymer needs to fulfil the following specifications in order to be used in a transdermal system.

1. The molecular weight, glass transition temperature, and chemical functionality of the polymer must allow the specific drug to diffuse and release.

2. A sizable amount of medication should be able to be included thanks to the polymer.

3. The polymer and the drug shouldn't interact chemically or physically.

B. Drug substance:

The development of a successful transdermal product depends on the selection of the appropriate drug substance. The following significant pharmacological traits affect how well it diffuses through the skin and the apparatus.

Chemical and physical characteristics:

· The molecular weight of the medication should be less than 600 Dalton.

· The log P should be in the range of 1 to 7.

· The melting point must be lower than 200 degrees Celsius.

· Two hydrogen bonding groups are required at minimum.

· The oil: water partition coefficient must be favorable.

· Drugs that are highly acidic or alkaline in solution should not be administered transdermally.

· Drugs should be soluble in mineral oil and water at concentrations greater than 1mg/ml.

C. Enhancers of Penetration:

· They are regarded as an essential component of the majority of transdermal formulations and increase skin penetration.

· They can alter the skin's resistance to penetration by reacting with the skin's surface or the applied substance.

The following qualities should be present in an ideal penetration enhancer:

1. Pharmacological inertness, affordability, and Cosmetically Acceptable.

2. Nontoxic.

3. Nonirritating.

4. Non allergenic.

5. Quick onset; predictable and appropriate duration of action for the medicine used, chemical penetration enhancers reversible impact on the stratum corneum's barrier properties.

6. Compatible with the delivery system both chemically and physically.

7. Easily fitted into the delivery system.

Two Types of Principles have been employed to increase Drug Permeation through Skin.

1. Physical Enhancers.

2. Chemical Enhancers.

1. Physical Enhancers:

When chemical enhancement's limitations were reached, physical enhancement technologies became popular.

Methodologies:

I. Electrically Based Techniques:

Electroporation, Ultrasound, Iontophoresis.

II. Structure Based Technique: Micro needles.

III. Velocity Based Technique: Jet-propulsion.

I. Electrically Based Techniques^6,7:

a) Iontophorosis: It works by creating a repulsion between the charged electrode and the solute. Current applied 0.5Ma/cm² Ex: Lidocaine, Vincristine.

Types of transdermal drug delivery system:

A. Single layer drug in adhesive: In this kind, the drug is present in the adhesive layer. The adhesive layer is in charge of delivering the medication onto the skin in addition to holding the several layers together. A backing and a temporary liner encircle the adhesive layer⁸.

B. multi-layer drug-in-adhesive: This type is caused by the sticky layer. In addition, this patch has a permanent backing and a temporary liner-layer^9,10.

C. Vapour patch: This kind of patch uses an adhesive layer that not only holds the different layers together but also as vapor is released. New to the market, vapor patches are frequently used to release essential oils during decongestion. There are numerous other kinds of vapor patches on the market that are intended to enhance sleep quality and lessen the effects of cigarette smoking.

D. Drug reservoir: In the reservoir system is situated between a rate-controlling membrane and an impermeable backing layer. The rate-controlling membrane, which may be micro porous or nonporous, is the only way the medication can escape. Drugs can be disseminated in a solid polymer matrix, in a solution, suspension, gel, or another form in the drug reservoir compartment. As a drug-compatible outer surface polymeric membrane, hypoallergenic adhesive polymer can be used^11,12.

E. Matrix system:

I. Drug-in-adhesive system: This kind creates a drug reservoir by dispersing the drug in an adhesive polymer, which is subsequently distributed on an impermeable backing layer by solvent casting or melting (for hot-melted adhesives). For protection, unmediated sticky polymer films are put on top of the reservoir¹³.

II. Matrix-dispersion system: In this kind, the medication is uniformly distributed within a matrix of hydrophilic or lipophilic polymers. In a compartment made of a drug-impermeable backing layer, this drug-containing polymer disk is fixed to an occlusive base plate. To create a strip of adhesive rim, the adhesive is placed around the outside of the drug reservoir rather than on its face^14,15.

F. Micro reservoir system:

aqueous solution of a water-soluble polymer and then uniformly spreading the solution in a lipophilic polymer¹⁶.

EVALUATION PARAMETERS:

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 medicine and excipients work together. To create a stable product, the medicine and the excipients must work well together. Therefore, it is essential to identify any potential physical or chemical interactions as they may impact the medication's stability and bioavailability. Compatibility studies are crucial to formulation development if the excipients are novel and haven't been utilized in formulations with the active ingredient.

2. The patch's thickness:

To guarantee 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.

3. Uniformity of weight:

Before testing, the created patches must be dried for four hours at 60°C. A predetermined patch area must be divided into various sections and weighed using a digital scale. From the individual weights, the average weight and standard deviation values must be determined.

4. Folding endurance:

A particular strip is to be cut uniformly and folded at the same spot repeatedly until it breaks. The value of folding endurance was determined by how many times the film could be folded in the same spot without breaking.

5. The Percentage Content of Moisture:

The produced films must be weighed separately and stored for 24 hours at room temperature in a dessicator filled with fused calcium chloride. The films must be reweighed after a day in order to calculate the moisture content as a percentage using the formula below.

[Initial weight-Final weight/Final weight] x 100 is the percentage moisture content.

6. Moisture uptake percentage:

To maintain 84% relative humidity, the weighed films must be stored in a desiccators with a saturated potassium chloride solution at room temperature for 24 hours. The films must be reweighed after a day in order to calculate the percentage moisture uptake using the formula below.

[Final Weight-Initial weight/Initial weight] x 100 is the percentage of moisture uptake.

7. Assessment of water vapour permeability (WVP): The foam dressing method can be used to measure water vapor permeability. A natural air circulation oven is used in place of an air-forced oven. The following formula can be used to calculate the WVP.

WVP = W/A

where A - the surface area of the exposed samples, given in m2, WVP is the quantity of vapour that permeated through the patch, expressed in gm/24 hours, and WVP is expressed in gm/m2 per 24 hours.

8. Content of drugs:

A certain volume of a suitable solvent must dissolve a defined patch area. After that, the solution must be filtered through a filter medium, and the drug content must be examined using the appropriate technology (either the UV or HPLC method). The average of three distinct samples is shown by each value.

9. Dosage unit uniformity test:

To fully extract the medicine from the patch, a precisely weighed amount of the patch must be chopped into small pieces, transferred to a volumetric flask, dissolved in an appropriate solvent, and fornicated. The patch must then be built up to the appropriate level using the same. After letting the resultant solution settle for approximately an hour, the supernatant was appropriately diluted with the right solvent to provide the required concentration. The drug content per piece will be determined after the solution was filtered using a 0.2m membrane filter and examined using an appropriate analytical method (UV or HPLC).

10. Drug release experiments in vitro:

The drug release from the produced patches can be evaluated using the paddle over disc method (USP equipment V). Dry films of a given thickness must be cut into precise shapes, weighed, and adhered to a glass plate. After that, the apparatus was equilibrated to 32± 0.5°C and the glass plate was submerged in 500 ml of the phosphate buffer or dissolving media (pH 7.4). After that, the paddle was positioned 2.5 cm away from the glass plate and turned at 50 rpm. 5-mL aliquots of samples can be taken out at suitable intervals for up to 24 hours and subjected to HPLC or UV spectrophotometer analysis. The goal of the experiment is to performed in triplicate and the mean value can be calculated^17-20.

New Developments in Transdermal Patch Technology:

Conventional transdermal patches are only used for medication release and storage. Traditional patching includes numerous difficulties and disadvantages, such as minimal release or restricted dosage, even though this approach has certain benefits. The field of transdermal medication delivery has seen a number of advancements to date. These include the creation of innovative patches with improved drug penetration and release, increased loading, and precise drug sensing and release capabilities. As will be covered below, transdermal medication delivery is an active research and development subject with a number of exciting new breakthroughs on the horizon.

SMART PATCHES:

Sensors and other technology built into smart patches allow them to track patient status and modify medication distribution as necessary. A team of researchers created a smart patch sensor technology in 2014 that uses micro needles to test blood sugar levels continuously and painlessly in diabetics. This patch immobilizes the glucose-specific c-enzyme glucose oxidase (GOx) and acts as an electrical mediator for glucose detection using a conducting polymer like poly (3,4-ethylenedioxythiophene) (PEDOT). After more investigation and development, a smart insulin-releasing patch with 121 microneedles and nanoparticles was created. The patch enters the interstitial fluid between subcutaneous skin cells without causing any pain. Insulin and the glucose-sensing enzyme glucose oxidase, which changes glucose into gluconate, are found in the nanoparticles in each needle.

Hypoxia-responsive polymers envelop these molecules. The hypoxia-responsive polymer detects the oxygen-depleted environment created by increased glucose oxidase activity in response to elevated glucose, as illustrated in Figure 4, which causes the nanoparticles to degrade and release insulin.

Wound healing is a complex and dynamic regenerative process with constantly changing physical and chemical parameters. It’s management and monitoring offer great benefits, especially for bedridden patients. Iversen et al. reported an inexpensive, flexible, fully printed smart patch on the skin to measure changes in wound pH and fluid volume. Such bendable sensors can also be easily incorporated into wound dressings. The sensor consists of various electrodes printed on a polydimethylsiloxane (PDMS) substrate for pH and humidity measurements. The generated sensor patch has a sensitivity of 7.1 ohm/pH to the wound pH value. Hydration sensor results showed that the water content of the semi-porous surface can be quantified by the change in resistivity 21-26.

Degradable/Dissolving Patches:

These patches don't need to be taken off and thrown away because they are made to dissolve on the skin. These patches are often composed of biodegradable substances that the body absorbs after use. Researchers successfully used a dissolving patch to provide the antibiotic gentamicin to a mouse model of bacterial infection in a proof-of-concept paper that was published in 2019. The findings demonstrated that Klebsiella pneumoniae infection might be managed by applying a microarray patch that dissolves gentamicin to mouse ears. Additionally, lysing patch-treated animals showed a lower bacterial burden in their lungs and nose-associated lymphoid tissue than untreated control mice. The micro needles in these patches are made out of biodegradable materials. After gentamicin has been released from the patch, the micro needle dissolve on the Skin layer.

Dissolving micro needles (MNs) are particularly effective at delivering vaccines and medications that are not very permeable. To effectively deliver insulin transdermally, a two-step injection and centrifugation procedure was employed to localize the insulin to the needle.

Insulin from MN patches had a relative pharmacological availability of 95.6% and a relative bioavailability (RBA) of 85.7%. In comparison to traditional subcutaneous injection, this study shows that using dissolving patches to deliver insulin results in a good relative bioavailability (RBA), proving the efficacy of dissolving patches for the treatment of diabetes^27-30.

Patches with High Loading/Release:

High drug loading and regulated drug release are necessary for long-acting transdermal medication administration. A new hydroxyphenyl (HP)-modified pressure-sensitive adhesive (PSA) was created to enhance drug-polymer miscibility and accomplish controlled drug release. The findings demonstrate that, in contrast to ionic and neutral H-bonds, the dual-ionic H-bonds between R (3)N and R (2) NH-type medications and HP-PSA are reversible and reasonably strong. As a result, patches were able to adjust the drug release rate from 1/5 to 1/2 and dramatically increase the drug loading from 1.5 to 7 times without affecting the overall release profile. According to pharmacokinetic studies, the HP-PSA-based high-load patch increased area under the concentration-time curve (AUC), prevented abrupt release, and increased average dwell duration by more than 6x, suggesting the possibility^31-33.

Potential Application of Transdermal Patches:

Nicodermis is a transdermal nicotine patch that aids in quitting smoking. In the United States, it is the most popular patch. Two opioid drugs that are available in patch form and are used to treat severe pain 24/7 are fentanyl (marketed as Duragesic) and buprenorphine (marketed as BuTrans). Estraderm patches containing estradiol are offered to treat postmenopausal osteoporosis and menopausal symptoms. For menopausal symptoms, it is also offered as Climara Pro, which combines it with levonorgestrel. Transdermal patches containing nitroglycerin are recommended as an alternative to sublingual tablets for treating angina pectoris. A clonidine transdermal patch is available to treat hypertension. The first transdermal delivery system for major depressive disorder was a transdermal patch containing selegiline (an MAO inhibitor). Methylphenidate is a transdermal medication used to treat attention deficit hyperactivity disorder (ADHD).

Transdermal Patches for Patches for Vaccination:

Transdermal patches are being developed by researchers to administer vaccines via the skin, perhaps providing a less painful and more convenient option than injections. The smallpox vaccine patch that uses micro needles is a prime example. Neutralizing antibodies were produced three weeks after the mice were immunized with this vaccination patch. IFN-γ secreting cells significantly increased, and levels were maintained for 12 weeks, indicating that the transdermal patch may be used as an alternate immunization and preservation delivery method. A different research team created a lytic micro needle patch that targets skin antigen-presenting cells in order to vaccinate against influenza. A bio-compatible polymer that contains an inactivated influenza virus vaccine was used to manufacture micro-needles, which can be inserted and dissolve in the skin in a matter of minutes. The patch produced intense-mice with cell-mediated immune responses and antibodies that offered total defense against deadly challenges. By employing a transdermal patch, the findings offer a novel method for safer, easier immunization with enhanced immunogenicity, which may allow for greater vaccination coverage^34-35.

Transdermal Patches for Gene Therapy:

Transdermal patches have recently been studied as a means of delivering genetic material to damaged cells through gene therapy. The goal of groundbreaking research was to concurrently transfer genes and photothermic drugs to the cancer cells. To achieve this, a two-step casting process was used to create transdermal patches co-loaded with p53 DNA and IR820, a near-infrared dye. Prior to p53 DNA and IR820 being mainly put onto the patches, hyaluronic acid was initially created as the matrix. The patches released p53 DNA and IR820 to subcutaneous tumor locations after effectively penetrating the stratum corneum and quickly dissolving. Because gene therapy and photothermal agents work in concert, the patch demonstrated a strong anti-tumor impact in vivo. These results show that a transdermal patch may be a promising strategy for subcutaneous tumor treatment^36-37.

Transdermal Patches for Insulin Delivery:

To treat diabetics, transdermal insulin delivery patches are used to transfer insulin through the skin and into the bloodstream. The pancreas secretes the hormone insulin, which helps control blood sugar levels in the body. Because they are unable to use the insulin their bodies produce efficiently or create enough of it, diabetics may have elevated blood sugar levels. To date, a number of novel methods for delivering insulin have been documented, such as the utilization of liposomes, ionic liquids, choline bicarbonate and geranic acid (CAGE), and nonmaterial’s. An easy and discrete substitute for conventional insulin delivery techniques like injections and insulin pumps is the use of transdermal patches. Usually placed on the skin of the thigh, upper arm, or belly, the patches are made to release a steady quantity of insulin over a predetermined amount of time.

Notably, creating transdermal patches for insulin delivery presents a number of difficulties. A big protein molecule, insulin is difficult for the skin to absorb. Using a water-swellable spherical double-layered micro needle (MN) patch at the tip, researchers have created a novel method for transdermal protein delivery in order to get around this. Through selective distal swelling following skin insertion, this design enables MNs to mechanically engage soft tissue. Furthermore, passive diffusion through the inflated tips allowed for the long-term release of laden proteins. After being submerged in saltwater for 12hours, insulin-loaded MN patches released 60% of their insulin, with about 70% of the released insulin seemingly maintaining its structural integrity. According to research on animals, swollen MN patches cause a sustained release of insulin, which gradually lowers blood glucose levels. All things considered, transdermal insulin delivery patches may offer diabetic patients a practical and efficient way to receive their medication. To maximize these products' effectiveness and safety, more study and development are necessary^38-44.

Transdermal Patches for Cardiovascular Diseases:

Because of the decreased cardiac ejection fraction in heart failure, pharmacokinetics (PK) and pharmacodynamics (PD) are often modified to account for hypo perfusion systemic situations. Renal failure also results in decreased medication metabolism and metabolite clearance. Additionally, medication absorption is hampered by hypoalbuminemia and hepatic congestion brought on by heart failure. Thus, a drug delivery solution is offered by transdermal patch delivery devices. Propranolol, for instance, is a beta-adrenergic blocker that is not selective. When given orally, it has a bioavailability of about 23% and significantly alters its hepatic first-pass metabolism. Oral propranolol produced a Cmax of 56.4mg/mL in 13.2 minutes, according to the findings of a prior animal investigation involving rabbits. However, its bioavailability was 12.3% because of the involvement of liver metabolism. However, after 8 hours of initial lag time, the transdermal propranolol patch recorded a bioavailability that was 74.8% higher than oral propranolol, with a steady-state plasma concentration (Css) of 9.3mg/ml^45-47.

Conversely, Bisono Tape is a transdermal patch that contains bisoprolol as its active ingredient and is used to treat atrial fibrillation, orthostatic hypotension from heart failure, premature ventricular contraction, and aortic dissection. The Cmax of the oedema group was 13.3mg/mL, whereas the Cmax of the non-oedematous group was 17mg/mL, according to a comparison of patients with and without edema using the Bisono Tape 4 mg patch. The purpose of this study was to determine how systemic edema affected critically ill patients' ability to absorb beta-blockers from skin patches. However, they found that systemic edema has no influence on blood levels or the heart rate-lowering effects of bisoprolol following application of the bisoprolol skin patch^48-50.

The hypertension medication clonidine is also administered by transdermal patch. The original purpose of clonidine, an α 2-adrenergic agonist, was to alleviate hypertension. Drug withdrawal syndrome and attention-deficit hyperactivity disorder (ADHD) were among the conditions for which it was utilized. Introduced in 1983, the FDA approved the transdermal clonidine patch in 1984. A comparative analysis of oral and transdermal clonidine has now been carried out. Transdermal clonidine had a longer half-life than oral clonidine (31.9 h vs. 10.8 h), however the results showed no change in Cmax between the two forms of clonidine (0.39ng/mL and 0.3ng/mL). Additionally, they demonstrated the same antihypertensive impact. Another medication being explored for transdermal administration is losartan, an angiotensin II receptor blocker (ARB). Proniosome transdermal medication delivery was previously devised and investigated in a rat skin investigation. When given orally, transdermal losartan was found to contribute to a Cmax of 152ng/mL and 141 ng/mL. Nonetheless, transdermal losartan has a 1.93-fold higher bioavailability than oral losartan^51-53.

Another medication that should be mentioned in cardiovascular therapy is nitroglycerin. In 1867, Lauder Blanton utilized nitroglycerin to treat angina pectoris and observed that the medication became resistant after several doses. Ferid Murad discovered that nitroglycerin's nitric oxide (NO) causes vasodilation by activating cyclic guanosine monophosphate (c GMP) in the vascular smooth muscle. Gale and Berggren created the first transdermal nitroglycerin patch in 1985 (Patent access US-4615699-A). Twenty-five healthy males were given Nitro-Dur and Nitro-Dur II, a different kind of nitroglycerin transdermal patch, in a two-way crossover study a year later. The average Cmax values were 0.383 ng/mL and 0.432ng/mL, respectively^54-55.

CONCLUSION:

In order to generate interest among the research scientists, this review article concluded that an older medicine may be formulated in a novel dosage form. A drug's TDDS is an efficient way to administer it. TDDS are becoming more and more popular, and researchers are taking notice. Many new medications will be developed in a transdermal form, but it's important to remember that the formulation may not change the skin's physiology. The drug reservoir, liners, adherents, backing laminates, permeation enhancers, plasticizers, and solvents are some of the fundamental parts of transdermal patches that are essential to the medication's skin release. Following transdermal patch manufacture, they are assessed for skin irritation, in-vitro penetration, and physicochemical investigations.

Future TDDS development will probably concentrate on expanding the number of drugs accessible for usage and increasing the control of the therapy regimen.

The size of TDDS in the local and international drug delivery system market has grown recently, as evidenced by an increase in research studies, patents, and commercially accessible goods from numerous businesses and research facilities. Furthermore, even among TDDS modalities, micro-needles are gaining a lot of attention. They combine the benefits of micro needles with the drawbacks of the current patch and simple application types of needles to achieve greater treatment efficacy and outcomes. Manufacturing and commercialization strategies are being developed for this, judiciously utilizing cutting-edge technology like 3D bioprinting. Developments in these TDDS’s may serve as the impetus for reducing the incidence of disorders affecting the central nervous and cardiovascular systems.

Diabetes, neurological conditions, genetic disorders, and viral and localized infections, all the while leading the way in immunization development and promoting patient choice for self-administration of medications for sustained care. TDDS is a realistic practical application as the next generation of drug delivery system^56-58.

ACKNOWLEDGMENT:

The authors would like to thank Principal, Malla Reddy College of Pharmacy, Maisammaguda, Secunderabad, Telangana for providing us with this opportunity and facilities to work on this review.

CONFLICTS OF INTEREST:

The authors declare there are no conflicts of interest.

REFERENCES:

1. Jain. Controlled and Novel Drug Delivery. CBS Publishers, and Distributors, 2002; 107.

2. Chowdary K.P.R and Naidu RAS. Transdermal Drug Delivery. A Review of Current Status, Indian Drugs, 1995; 32(9):414-422.

3. Hadgraft J Guy R.H. Transdermal Drug Delivery, New York: Marcel Dekker, 2nd Ed; 35:14-16.

4. Hadgraft JW, and Somers G.F. Review Article Percutaneous absorption, International Journal of Pharmaceutics. 2005; 305:2-12

5. AC Williams, BW Barry. Penetration enchancers. Adv Drug Delivery Rev. 2012; 64(5): 128-137.

6. G.K Menon New Insights into skin structure: scratching the surface Adv Drug Delivery Rev. 2002; 5(4): 13-17.

7. HA Benson AC Watkinson Topical and Transdermal Drug Delivery: principles and practice Wiley Hoboken, NJ, USA.2012.

8. Heather AE. Transdermal drug delivery: penetration Enhancement Techniques. Current Drug Delivery. 2005; (2): 23-33.

9. Singh MC, Naik AS, Sawant SD, Transdermal drug delivery system with major emphasis on transdermal patches: a review. J Pharm Res. 2010; 3(10):2537-2543.

10. M Imani F Lahooti- Fard SM Taghizadeh M Tarkrousta Effect of adhesive layer thickness and drug delivery system. AAPS Pharm Sci. 2011; 326-334.

11. P Kumar C Sankar B Mishra Delivery of macromolecules through skin Indian Pharm. 2004; 5(3): 717.

12. OA AI Hanbali HMS Khan M Sarfar M Arafat Ijaz Hameed Transdermal patches: Design and current approaches to painless drug delivery Acta Pharm. 2019; 69219715

13. S Dhiman TG Singh AK Rehni Transdermal patches; a recent approach to new drug delivery system J Pharm Sci 2011;326-334

14. S Rani K Saroha N Syan P Mathur Transdermal patches a successful tool in transdermal drug delivery system; an overview. Der Pharm SINICA. 2011; 2: 17-29.

15. A Arunachalam M Karthikeyan D V Kumar M Prathap S Sethuram A S Kumar Tansdermal drug delivery system: A review. Current Pharma Res. 2010; 1(4):70-81.

16. CL Stevenson JT Satini R Langer Reserviour-based drug delivery system utilizing microtechnology. Adv Drug Delivery Rev. 2012; 6(4): 590-602.

17. Koteshwar K.B, Udupa N and Vasanthab Kumar, Desgin and Evaluation of Captopril Transdermal Preparations, Indian Drugs. 2020; 15(29): 680-685.

18. Priyanka Arora, Biswajit Mukherjee. Design Development Physiochemical and in-vitro. Evaluation of Tansdermal Patches Containing Diclopenac Diethylammonium Salt, Journal of Pharmaceutical Sciences. 2002: 91(9): 2076-2089.

19. Sankar V, VelrajanG, Palanippan R and Rajasekar S, Desgin and Evaluation OF Nifedipine Transdermal Patches, Indian Journal of Pharmaceutical Sciences. 2003; 65(5): 510-515.

20. Manvi F, V, Dandagi P.M, Gadad A.P, Mastiholimat VS and Jagdeesh T. Formulation of Transdermal Drug Delivery System of Ketotifen Furamate, Indian Journal of Pharmaecutical Sciences. 2013; 65(3): 239-24.

21. Invernale MA, Tang BC, York RL, Le L, Hou DY, Anderson DG. Microneedle electrodes toward an amperometric glucose-sensing smart patch. Adv. Health Matter. 2014; 3: 338–342.

22. Veiseh O, Langer R. Diabetes: A smart insulin patch. Nature. 2015; 524: 39–40.

23. Yu J., Zhang Y., Ye Y., DiSanto R., Sun W., Ranson D., Ligler F.S., Buse J.B., Gu Z. Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery. Proc. Natl. Acad. Sci. USA. 2015; 112:8260–8265.

24. Iversen M., Monisha M., Agarwala S. Flexible, Wearable and Fully-printed Smart Patch for pH and Hydration Sensing in Wounds. Int. J. Bioprinting. 2022; 8:447.

25. Liu H., Li Z., Che S., Feng Y., Guan L., Yang X., Zhao Y., Wang J, Zvyagin A.V., Yang B., et al. A smart hydrogel patch with high transparency, adhesiveness and hemostasis for all-round treatment and glucose monitoring of diabetic foot ulcers. J. Mater. Chem. B. 2022; 10:5804–5817.

26. Gilpin V., Surandhiran D., Scott C., Devine A., Cundell J.H., Gill C.I.R., Pourshahidi L.K., Davis J. Lasered Graphene Microheaters Modified with Phase-Change Composites: New Approach to Smart Patch Drug Delivery. Micromachines. 2022; 13:1132.

27. Rodgers A.M., McCrudden M.T.C., Courtenay A.J., Kearney M.C., Edwards K.L., Ingram R.J., Bengoechea J., Donnelly R.F. Control of Klebsiella pneumoniae Infection in Mice by Using Dissolving Microarray Patches Containing Gentamicin. Antimicrobial. Agents Chemother. 2019; 63:12-18.

28. Lee IC, Lin W.M., Shu J.C., Tsai S.W., Chen C.H., Tsai M.T. Formulation of two-layer dissolving polymeric microneedle patches for insulin transdermal delivery in diabetic mice. J. Biomed. Mater. Res. Part A. 2017; 105:84–93. Doi: 10.1002/jbm.a.35869.

29. Kim H., Seong K.Y., Lee J.H., Park W., Yang S.Y., Hahn S.K. Biodegradable Microneedle Patch Delivering Antigenic Peptide-Hyaluronate Conjugate for Cancer Immunotherapy. ACS Biomater. Sci. Eng. 2019; 5:5150–5158.

30. Li Y., Liu F., Su C., Yu B., Liu D., Chen H.J., Lin D.A., Yang C., Zhou L., Wu Q., et al. Biodegradable Therapeutic Microneedle Patch for Rapid Antihypertensive Treatment. ACS Appl. Mater. Interfaces. 2019; 11:30575–30584.

31. Zhang S., Liu C., Song Y., Ruan J., Quan P., Fang L. High drug-loading and controlled-release hydroxyphenyl-polyacrylate adhesive for transdermal patch. J. Control. Release. 2023; 353:475–489.

32. Yang D., Liu C., Piao H., Quan P., Fang L. Enhanced Drug Loading in the Drug-in-Adhesive Transdermal Patch Utilizing a Drug-Ionic Liquid Strategy: Insight into the Role of Ionic Hydrogen Bonding. Mol. Pharm. 2021;18: 1157–1166.

33. Yang D., Liu C., Quan P., Fang L. Molecular mechanism of high capacity-high release transdermal drug delivery patch with carboxyl acrylate polymer: Roles of ion-ion repulsion and hydrogen bond. Int. J. Pharm. 2020.

34. Choi I.J., Cha H.R., Hwang S.J., Baek S.K., Lee J.M., Choi S.O. Live Vaccinia Virus-Coated Microneedle Array Patches for Smallpox Vaccination and Stockpiling. Pharmaceutics. 2021; 13:209.

35. Sullivan S.P, Koutsonanos D.G., Del Pilar Martin M., Lee J.W., Zarnitsyn V., Choi S.O., Murthy N., Compans R.W., Skountzou I., Prausnitz M.R. Dissolving polymer microneedle patches for influenza vaccination. Nat. Med. 2010; 16: 915–920.

36. Singh P., Muhammad I., Nelson N.E., Tran K.T.M., Vinikoor T., Chorsi M.T., D’Orio E., Nguyen T.D. Transdermal delivery for gene therapy. Drug Deliv. Transl. Res. 2022; 12:2613–2633.

37. Xu Q., Li X., Zhang P., Wang Y. Rapidly dissolving microneedle patch for synergistic gene and photothermal therapy of subcutaneous tumor. J. Mater. Chem. B. 2020;8: 4331–4339.

38. Islam M.R., Uddin S., Chowdhury M.R., Wakabayashi R., Moniruzzaman M., Goto M. Insulin Transdermal Delivery System for Diabetes Treatment Using a Biocompatible Ionic Liquid-Based Microemulsion. ACS Appl. Mater. Interfaces. 2021; 13: 42461–42472.

39. Jorge L.R., Harada L.K., Silva E.C., Campos W.F., Moreli F.C., Shimamoto G., Pereira J.F.B., Oliveira J.M., Jr., Tubino M., Vila M., et al. Non-invasive Transdermal Delivery of Human Insulin Using Ionic Liquids: In vitro Studies. Front. Pharmacol. 2020; 11:243

40. Lin X., Choi D., Hong J. Insulin particles as building blocks for controlled insulin release multilayer nano-films. Mater. Sci. Eng. C Mater. Biol. Appl. 2015; 54:239–244.

41. Maciel V.B.V., Yoshida C.M.P., Pereira S., Goycoolea F.M., Franco T.T. Electrostatic Self-Assembled Chitosan-Pectin Nano- and Microparticles for Insulin Delivery. Molecules. 2017; 22:1707.

42. Tanner E.E.L., Ibsen K.N., Mitragotri S. Transdermal insulin delivery using choline-based ionic liquids (CAGE) J. Control. Release. 2018; 286:137–144.

43. Sugumar V., Ang K.P., Alshanon A.F., Sethi G., Yong P.V.C., Looi C.Y., Wong W.F. A Comprehensive Review of the Evolution of Insulin Development and Its Delivery Method. Pharmaceutics. 2022; 14:1406.

44. Seong K.Y., Seo M.S., Hwang D.Y., O’Cearbhaill E.D., Sreenan S., Karp J.M., Yang S.Y. A self-adherent, bullet-shaped microneedle patch for controlled transdermal delivery of insulin. J. Control. Release. 2017; 265:48–56.

45. Ogawa R., Stachnik J.M., Echizen H. Clinical pharmacokinetics of drugs in patients with heart failure: An update (part 1, drugs administered intravenously) Clin. Pharmacokinet. 2013; 52:169–185.

46. Lainscak M., Vitale C., Seferovic P., Spoletini I., Cvan Trobec K., Rosano G.M. Pharmacokinetics and pharmacodynamics of cardiovascular drugs in chronic heart failure. Int. J. Cardiol. 2016; 224:191–198.

47. Mangoni A.A., Jarmuzewska E.A. The influence of heart failure on the pharmacokinetics of cardiovascular and non-cardiovascular drugs: A critical appraisal of the evidence. Br. J. Clin. Pharmacol. 2019;85:20–36.

48. Ahad A., Aqil M., Kohli K., Sultana Y., Mujeeb M., Ali A. Interactions between novel terpenes and main components of rat and human skin: Mechanistic view for transdermal delivery of propranolol hydrochloride. Curr. Drug Deliv. 2011; 8: 213–224.

49. Corbo M., Liu J.C., Chien Y.W. Bioavailability of propranolol following oral and transdermal administration in rabbits. J. Pharm. Sci. 1990; 79:584–587.

50. Matsuoka H., Kuwajima I., Shimada K., Mitamura H., Saruta T. Comparison of efficacy and safety between bisoprolol transdermal patch (TY-0201) and bisoprolol fumarate oral formulation in Japanese patients with grade I or II essential hypertension: Randomized, double-blind, placebo-controlled study. J. Clin. Hypertens. 2013;15: 806–814

51. Hara T., Yagi S., Akaike M., Sata M. Transdermal patch of bisoprolol for the treatment of hypertension complicated with aortic dissection. Int. J. Cardiol. 2015; 198: 220–221.

52. Shinohara M., Fujino T., Koike H., Kitahara K., Kinoshita T., Yuzawa H., Suzuki T., Fukunaga S., Kobayashi K., Aoki J., et al. Assessment of a novel transdermal selective beta1-blocker, the bisoprolol patch, for treating frequent premature ventricular contractions in patients without structural heart disease. J. Cardiol. 2017; 70:212–219

53. Kiuchi S, Hisatake S, Kabuki T, Oka T, Dobashi S., Fujii T., Sano T., Ikeda T. Bisoprolol transdermal patch improves orthostatic hypotension in patients with chronic heart failure and hypertension. Clin. Exp. Hypertens. 2020; 42:539–544.

54. Yasui T, Oka T, Shioyama W, Oboshi M, Fujita M. Bisoprolol transdermal patch treatment for patients with atrial fibrillation after noncardiac surgery: A single-center retrospective study of 61 patients. SAGE Open Med. 2020; 8: 7817.

55. Takahashi Y, Sonoo T, Nakano H., Naraba H., Hashimoto H., Nakamura K. The influence of edema on the bisoprolol blood concentration after bisoprolol dermal patch application: A case-control study. Medicine. 2021.

56. Ch. Nagadev, M. Durga Srinivasa Rao, P. Venkatesh, D. Hepcykalarani, R. Prema. A Review on Transdermal Drug Delivery Systems. Asian J. Res. Pharm. Sci. 2020; 10(2):109-114.

57. Saudagar RB, Samuel S. Ethosomes: Novel noninvasive carrier for Transdermal Drug Delivery. Asian J. Pharm. Tech. 2016; 6(2): 135-38.

58. Roge Ashish B, Sakhare Ram S, Bakal RL, Channawar MA, Bakde BV, Gawande SR, Chandewar AV. Ethosomes: Novel Approach in Transdermal Drug Delivery System. Research J. Pharma. Dosage Forms and Tech. 2010; 2(1): 23-27.

Received on 27.01.2025 Revised on 11.03.2025

Accepted on 16.04.2025 Published on 08.07.2025

Available online from July 12, 2025

Asian J. Pharm. Tech. 2025; 15(3):312-320.

DOI: 10.52711/2231-5713.2025.00047

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.