Systemic arterial hypertension, commonly referred to as hypertension, is characterized by persistently high blood pressure in the systemic arteries. Blood pressure is typically expressed as the ratio of systolic blood pressure—the pressure exerted on artery walls during heartbeats—to diastolic blood pressure. The thresholds for diagnosing hypertension can vary depending on the measurement methods used. Hypertension can result from a variety of underlying causes (Gupta, 2004). In the US, the prevalence of hypertension among adults ranges from 44% to 49%. Addressing hypertension in women could potentially reduce overall population mortality by approximately 7.3%, compared to 0.1% for hyperlipidemia, 4.1% for diabetes, 4.4% for cigarette smoking, and 1.7% for obesity, based on self-reported data from a survey of 533,306 adults. For men, eliminating hypertension could lead to a population mortality reduction of nearly 3.8%, in contrast to 2.6% for obesity, 1.7% for diabetes, 5.1% for cigarette smoking, and 2.0% for hyperlipidemia (Carey et al., 2022). The classes of angiotensin receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACE inhibitors), calcium channel blockers (CCBs), and thiazide-type diuretics may be selected for the first-line therapy of hypertension. The chance of cardiovascular events is decreased by all antihypertensive classes. Patients with hypertension find it difficult to adhere to their treatment plans when utilizing conventional dosage forms, such as pills, capsules, and injections. In addition to having a needle allergy, children with hypertension have difficulty taking their prescriptions. The majority of antihypertensive medications are administered as tablets; nevertheless, tablets have a number of drawbacks, including as stomach discomfort, drug breakdown in the stomach, uneven absorption, and pre-systemic drug metabolism, which ultimately results in reduced bioavailability (Li et al., 2021; Chen et al., 2022).  Antihypertensive medications can be administered via transdermal microneedle (MN)-based drug delivery devices, which helps to some extent to resolve these problems. The MN-based transdermal medication delivery system circumvents the limitations of the oral and injectable routes because the needles are non-invasive, inexpensive, and simple to use. These are extremely small needles, less than 1000 µm in diameter, that are able to pass through the main skin barriers that prevent medication molecules from passing through the stratum corneum without producing pain. With less frequent dosing and more convenient administration, MN systems can increase patient compliance by precisely localizing drugs and achieving improved biodistribution with efficacy. The restricted water solubility of antihypertensive drugs poses a serious challenge to their therapeutic use (Sartawi, et al., 2022; Halder et al., 2021).

Pathophysiology of hypertension

Hypertension is rooted in complex pathophysiological mechanisms with a significant genetic component. Various genes contribute to primary hypertension, with certain allelic variations linked to an increased risk, often accompanied by a family history of the condition. While genetics play a key role, environmental factors such as high sodium intake, excessive alcohol consumption, sleep apnea, poor sleep quality, and high mental stress also exacerbate the condition. Additionally, the risk of developing hypertension increases with age due to progressive stiffening of the arterial vasculature, influenced by factors like atherosclerosis and gradual changes in vascular collagen. Immunological factors may also be crucial, especially in the presence of rheumatological or viral conditions like rheumatoid arthritis. The intricate pathophysiology of hypertension is further elucidated by the mosaic theory (Burnier and Wuerzner, 2015).

The majority of the time, no symptoms exist. Most people discover they have high blood pressure when they go to the doctor or get their blood pressure checked elsewhere. People can acquire heart disease and renal problems without realizing they have high blood pressure because there are no signs. Malignant hypertension is a type of extremely high blood pressure that can be fatal. Among the symptoms could be:

• Confusion
• Vision changes
• Severe headache
• Nausea and vomiting
• Nosebleeds

Diagnosis of hypertension

The medical history comprises the following: (i) the length of time and previous blood pressure levels; (ii) the use of medications or substances that can elevate blood pressure (e.g., cocaine, amphetamines, oral contraceptives, steroids, non-steroidal anti-inflammatory drugs, erythropoietin, cyclosporine, nasal drops, liquorice); (iii) the amount of smoking and physical activity; (iv) gaining too much weight; (v) eating too much fat, salt, and alcohol; (vi) coexisting conditions like heart failure, cerebrovascular or peripheral vascular disease, diabetes mellitus, renal disease, gout, dyslipidemia, asthma, or any other serious illnesses, as well as medications used to treat those ailments; (vii) the outcomes and side effects of prior antihypertensive medication; (viii) the need to investigate sleep apnea syndrome symptoms.

The physical examination should encompass the following assessments: (i) palpation of the kidneys to check for conditions such as polycystic kidney disease; (ii) auscultation of abdominal murmurs to detect renovascular hypertension; (iii) auscultation of heart sounds and murmurs to identify potential aortic coarctation or aortic stenosis; (iv) examination of murmurs over the neck arteries; (v) evaluation for motor or sensory neurological defects; (vi) detection of abnormal cardiac rhythms or ventricular gallop; (vii) assessment for pulmonary rales; (viii) inspection for fundoscopic abnormalities in the retina; (ix) evaluation of intravascular volume status by estimating jugular venous pressure and checking for peripheral edema; (x) examination of pulses in the lower extremities for absence, reduction, or asymmetry, and identification of ischemic skin lesions; (xi) measurement of body weight, waist circumference, and body mass index. Moreover, during a hypertensive crisis, it is essential to monitor the patient’s blood pressure, oxygen saturation, and heart rate and rhythm (Papadopoulos et al., 2010).

Non Pharmacological treatment of hypertension

Weight Loss

If a patient is overweight or obese, losing weight can help lower blood pressure and cut down on the amount of prescription medications they need to take. Studies on long-term weight loss have shown that a 10 kg weight loss is linked to an average drop in systolic blood pressure of 6 mmHg and diastolic blood pressure of 4.6 mmHg (Cohen, 2017).

Physical Activity

Frequent aerobic activity resulted in an average 4 mmHg systolic and 3 mmHg diastolic blood pressure reduction. Therefore, the patient is advised to engage in 90–150 minutes of aerobic or resistance training per week. Therefore, it is recommended that all hypertension patients exercise (Diaz and Shimbo, 2013).

High Fiber and Low fat Diet

Consuming a diet high in low-fat foods and low in saturated fat, together with enough of fruits and vegetables, potassium, magnesium, and calcium, is a dietary strategy to lower blood pressure (DASH). decreased the patient's systolic blood pressure by 11.4 mmHg and their diastolic blood pressure by 5.5 mmHg. Consuming a diet rich in fruits and vegetables not only lowers blood pressure but also enhances endothelial function (Dodson et al., 1983).

Cutting down Alcohol intake

Reducing alcohol consumption to a reasonable level—? 2 drinks daily for males and < 1>

Pharmacological Treatments

Beta-adrenoreceptor blockers

By decreasing cardiac output, heart rate, renin release, and the effects of adrenergic regulation on the neurological system, beta-adrenoreceptor blockers lower blood pressure. When these comorbidities are absent, beta-adrenoreceptor blockers are less effective than other first-line antihypertensives in lowering the morbidity and mortality of cardiovascular disease (CVD). However, they do improve outcomes after acute myocardial infarction and in patients with heart failure who have a reduced left ventricular ejection fraction (Thadani, 1983).

Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers

Angiotensin II receptor blockers and ACE inhibitors are first-line antihypertensives among drugs that inhibit the RAAS; other antihypertensive drugs that target the RAAS, such as direct renin inhibitors and mineralocorticoid receptor antagonists, are typically reserved for use as first-line antihypertensive therapy due to a lack of clinical trial evidence (Piepho, 2000).

Thiazide-type and thiazide-like diuretic

Whereas thiazide-like diuretics, such as chlorthalidone, metolazone, and indapamide, lack the benzothiadiazine structure, thiazide-type diuretics, like hydrochlorothiazide, have a benzothiadiazine ring. Since the earliest trials demonstrating the morbidity benefits of antihypertensive medication, both subclasses of thiazide diuretics have been a key part of pharmacological hypertension management. They promote natriuresis by inhibiting Na+ and CIcotransporters in renal tubules (Liang et al., 2017).

Dihydropyridine calcium channel blockers

Dihydropyridine calcium channel blockers work by obstructing the L-type calcium channels in vascular smooth muscle, which causes vasodilation. They have been through numerous large-scale clinical trials and are proven antihypertensive medications. This pharmacological class has the practical benefit of being able to be taken with all other first-line anti-hypertensives (Meredith and Elliott, 2004).

Transdermal drug delivery for hypertension

Antihypertensive medications that were previously required to be administered two to four times daily can now be administered once daily thanks to innovative controlled-release drug delivery systems. Reduced dosage frequency and overall daily dose, convenience, improved compliance, and fewer adverse effects (achieved by lowering peak blood levels and producing steady blood levels) are some of the potential advantages. Maybe the novel delivery systems can affect the 24-hour blood pressure pattern and alter the blood pressure and heart rate increases in the morning, which would lower the frequency of ischemia episodes, which are more common during that time. The delayed attainment of pharmacodynamic impact, variable or decreased bioavailability, accelerated first-pass hepatic metabolism, dosage dumping, prolonged toxicity, dose inflexibility, and overall higher cost are some potential drawbacks of oral controlled-release medicines. Transdermal medication delivery offers a continuous, regulated, transcutaneous delivery of medicine and prevents presystemic metabolism, even though dermatologic responses are common (Prisant et al., 1992; Sharma and Sharma, 2023).

Transdermal patch

A transdermal patch is a medicated patch that can be applied topically to provide medication at a specified rate directly into the bloodstream via the layers of skin. Actually, the most practical way to administer is via patches. Because they are non-invasive, patients can cease the treatment at any moment during the course of several days. They have various sizes and are made up of several substances. Through diffusion processes, the patch can introduce active substances into the systemic circulation once it is put to the skin. High concentrations of active ingredients that stay on the skin for a long time may be present in transdermal patches.  The nitroglycerin patch was one of the earliest transdermal patches created in 1985. The patch is based on a rate-controlling ethylene vinyl acetate membrane that was created by Gale and Berggren. Many medications are currently offered as transdermal patches, such as nicotine, fentanyl, clonidine, scopolamine (hyoscine), and estradiol combined with norethisterone acetate. The application site may change based on the drug's therapeutic category. For instance, one can apply estradiol to the abdomen or buttocks and nitroglycerin to the chest. Moreover, the length of the drug's release varies according on usage, ranging from the shortest (up to 9 hours) to the longest (up to 9 days) (Al Hanbali  et al., 2019; Wong et al., 2023).

Advantages of transdermal patch

1. There is no intestinal metabolism, salivary metabolism, or hepatic first-pass metabolism.
2. Patients can self-administer these systems due to their ease of use.
3. In an emergency, drug intake can be immediately stopped during therapy by removing the patch at any time.
4. There is very little difference between and among patients because practically all individuals have the same structural and biochemical makeup of skin.
5. It is appropriate to deliver medications through the skin if they cause gastric discomfort and absorption (Sonkar et al., 2018).
6. Components of transdermal patch
7. Some of the components used for transdermal patch are

• Liner:

Removed prior to use, it provides storage patch protection. Take polyester film, for instance.

• Drug:

It comes into direct touch with the release layer. For instance, estrogen, methotrexate, and nicotine.

• Adhesive:

The adhesive property aids in the bonding of the patch's components as well as the adhesion of the patch to the skin.  As an illustration, consider silicones, polyisobutylene, and acrylates.

• Membrane:

It facilitates the drug's release from multilayer patches and reservoirs.

• Backing:

It shields the patch from the environment. For instance, polyvinyl alcohol and derivatives of cellulose

       
           
       
    Figure no 2 : Diagrammatic illustration of transdermal patch

MECHANISM ACTION OF TRANSDERMAL PATCH

Electroporation

One technique for applying brief, high-voltage electrical pulses to the skin is called electroporation. The skin's permeability for drug diffusion increases four orders of magnitude following electroporation. It is thought that drug transport happens through the temporary aqueous holes created by the electrical pulses in the stratum corneum.

Lontophoresis

Drug administration over the barrier is facilitated by iontophoresis, which applies a few milliamperes of current to a few square centimeters of skin through the electrode in contact with the formulation. primarily used in conjunction with pilocarpine administration to cause perspiration as a diagnostic test for cystic fibrosis. For a quick onset of anesthesia, iontophoretic delivery of lidocaine seems to be a promising method.

Application of ultrasound

It has been demonstrated that using ultrasound, especially low frequency ultrasound, improves the transdermal delivery of a variety of medications, including macromolecules. Another name for it is sonophoresis (Dhiman et al., 2011; Prabhakar et al., 2013).

Components of transdermal patch

Polymer Matrix

Polymers that are used for transdermal drug delivery must possess following characteristics:

• The polymer's molecular mass, physical characteristics, and chemical makeup should permit the passage of medication at the necessary rate.
• The polymer ought to be inert chemically.
• The polymer cannot break down while the device is in use.
• Polymer should enable the addition of numerous medications.
• It ought to be reasonably priced.
• The most widely utilized polymers are alginate, hydroxyl propyl methyl cellulose, cellulose acetate nitrate, eudragit, and polypropylene. (Sharma et al., 2020)

Penetration Enhancers

These are chemicals that modify the stratum corneum, making it easier for medications to pass through and enter the bloodstream. Certain substances interact with the stratum corneum, whilst other compounds improve the lipids' ability to permeate the cells in the stratum corneum. Terpenes, sulphoxide, fatty alcohols, surfactants, urea, and terpenes are examples of permeation enhancers that are often utilized.

Release Liner

The transdermal patch is designed to be removed from this component before being applied to the skin. As release liners, fluoropolymers and linear fluoroacrylates are frequently utilized (Saroha et al., 2011).

Drug

• The drug's first pass metabolism need to be higher.
• Medication with a limited therapeutic window
• Medicines have a brief half-life

Plasticizer

• It is also compatible with all other compounds in the formulation and is chemically inert. For example, di-butyl phthalate, tri-ethyl citrate, PEG, and PG.
• A portion of the plasticizer also serves as an enhancer of penetration. such as propylene glycol.
• They provide transdermal patches their flexibility.

Backing Laminate

This component is often made of inert materials, such as polyisobutylene, ethyl vinyl alcohol, etc., that permit moisture and oxygen to pass through while not interfering with the drug release process (Jatav et al., 2011).

Other Excipients

In addition to the components listed above, there are additional excipients such as drug dispersion solvents (methanol, dichloromethane, water, acetone, etc.). Additionally, plasticizers are frequently used in concentrations of 5–20% to improve plasticity.

Types of TDDS (Saikumar et al., 2012; Wiechers, 1992; Bhairam et al., 2012)

Single-layer drug-in-adhesive:

The medication is also included in this system's sticky layer. The adhesive layer in this kind of patch releases the medication in addition to holding the system as a whole and the individual layers to the skin together. There is a backer and a temporary liner all around the adhesive layer.

Multi-layer drug-in-adhesive:

Similar to a single-layer approach, a multi-layer drug inadhesive patch releases the medication through the action of both adhesive layers. The multi-layer method differs, though, in that it incorporates an additional drug-inadhesive layer, which is often (but not always) divided by a membrane. This patch also features a permanent backing and a transient liner-layer.

Reservoir:

The reservoir transdermal system differs from single-layer and multi-layer drug-inadhesive systems in that it features a distinct drug layer. The drug layer is an adhesive-separated liquid compartment that holds a drug solution or suspension. The backing layer also supports this patch. The rate of release in this kind of system is zero order.

Matrix:

In the Matrix system, the drug layer consists of a semisolid matrix that contains either a drug solution or suspension. This layer is partially covered by an adhesive layer that helps to secure the medication in place.

Vapour patch:

In this type of patch, the adhesive layer not only binds the various components together but also releases vapor. The latest innovations include vapor patches that can emit essential oils for up to six hours. These vapor patches are mainly utilized for decongestion and essential oil diffusion. Another variant, known as controller vapor patches, is designed to improve sleep quality. Additionally, there are vapor patches available that help reduce a smoker's monthly cigarette consumption.

Various methods for preparing transdermal patch  (Panchagnula, 1997)

Mercury substrate method

Using this approach, the medication is dissolved in a polymer solution together with additional ingredients and plasticizer. After stirring the solution combination for ten to fifteen minutes to create a uniform dispersion, it is poured onto a mercury surface that has been leveled. By putting a funnel over the surface inverted, the rate of evaporation can be adjusted.

By using IPM membrane method

Using a magnetic stirrer, the medication is mixed with solvents such water and propylene glycol, which already contains carbomer 940 polymers, and swirled for 12 hours. The addition of triethanolamine to the combination above results in neutralization and the formation of a viscous solution, or gel, which is then integrated onto the IPM membrane.

By using free film method

Casting on the mercury surface creates the cellulose acetate free film. To produce a 2% w/w polymer solution, chloroform is used. Plasticizer is added to the polymer solution after being precisely weighed at 40% weight per weight of polymer. Glass petridish with 5 milliliters of polymer solution on top of mercury sulphate. Following the solvent's evaporation, the free film formation on the mercury surface was noticed. The dried film is gathered and kept in a desiccator in between wax paper sheets. By adjusting the volume of the polymer solution, free films with varying thicknesses can be created.

Circular Teflon method

The polymers are simply dissolved in organic solvents to create the polymer solution. The medication is dissolved or dispersed in half the volume of the same organic solvents that are used to make the polymer solution. The enhancer is contained in the other half of the organic solvents. Next, the enhancer combination, drug solution, and polymer solution are combined, and Di-Nbutylpthalate is added as a plastisizer to this mixture. To manage the vaporization of solvent in laminar flow, the aforesaid combination is agitated for 12 hours before being poured into a circular Teflon mould that is set on a level surface and has the funnel covered in an inverted position (hood model). For a full day, the air speed is kept constant at 0.5 m/s. After that, the dried films are kept in silica gel-filled desiccators at 25 +/-0.5°C for a further 24 hours. Within a week of its creation, this kind of film is assessed.

Asymmetric TPX membrane method

Step1

This membrane is made by a wet or dry inversion technique. After TPX of the necessary quality is obtained, it is dissolved in a combination of solvents and non-solvent additives. A constant temperature of 60°C is maintained. Once the polymer solution is set aside at 40°C for 24 hours, it will form. After that, the polymer solution is poured onto a glass plate, and a garden knife is used to preserve the thickness. The film is evaporated at 50°C for 30 seconds following the casting process. Following that, the glass plates are submerged in a coagulation bath that is kept at a constant 25°C. The membrane is removed after ten minutes, and it is dried for twelve hours at 50°C in the oven.

Step2

The medication is distributed into the backing laminate, which is a heat-sealable polyester sheet (1009, 3m) with a concave 4 cm in diameter. Step Three After that, an asymmetric TPX [poly (4-methyl-1-pentene)] membrane is placed over it, and adhesive is used to seal it.

Step3

After that, an asymmetric TPX [poly (4-methyl-1-pentene)] membrane is placed over it, and adhesive is used to seal it.

Evaluation of transdermal patch

Drug-polymer Interaction studies

This metric is utilized to assess potential interactions between the drug and the polymer that is suggested to be employed in the development of transdermal drug delivery devices. Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) are the methods used in this test.

Patch Thickness

The goal of this patch is to keep transdermal compositions consistent. It is ascertained by using a micrometer to measure the patch's thickness at three different locations. (Baggi, 2018).

Uniformity of Patch

Mass. The average weight and standard deviation were computed after weighing each of the ten patches separately. The criterion for admission states that no weight should deviate significantly from the mean weight (Hussain, 2016).

Percent Moisture content

The films should be individually weighed and then stored for 24 hours at room temperature in a desiccator containing fused calcium chloride. After this period, the films need to be weighed again to determine the percentage moisture content using the following formula:

Percentage Moisture Content=(Initial Weight?Final Weight)/Final Weight ×100

In vitro penetration test

The Franz diffusion cell method can be used to perform an in vitro patch penetration test to assess drug permeability through mouse skin. To remove the sticking tissue or blood vessels that would subsequently serve as the membrane in the Franz diffusion cell procedure, the skin around the rat's stomach had to first be meticulously cleansed with distilled water. This device is made up of a water jacket, a donor compartment, and a receptor chamber. The Franz diffusion cell runs at a steady temperature thanks to the water jacket. Rat skin is inserted into the donor and receptor compartments with the epidermis facing up. Phosphate saline buffer pH 7.4 ±0.5 was the medium utilized, and a thermostatically controlled heater was employed to maintain the cell temperature at 37±0.5 °C. The volume is periodically removed from the receptor compartment at a specific minute and replaced with fresh media of the same volume. Following a filtering medium filter, the sample was examined using spectrophotometry or HPLC (Beedha et al., 2018).

Stability test

To observe and assess changes to the patch under all environmental conditions during storage and use, stability tests are carried out. The International Conference on Harmonization's (ICH) rules were followed in conducting this test. After six months of storage at 40±0.5°C and 75±5% relative humidity, patch samples were examined at0,30,60,90, and 180 days, and their drug content was determined.

In vitro Drug Release

USP equipment VII (reciprocating disc device) or apparatus V (paddle over disc) are used to evaluate in vitro the release of medications from transdermal. Diffusion cells, such as Franz diffusion cells, are also frequently employed in in vitro drug release investigations. Numerous mathematical models have been established to express the kinetics of drug release from a transdermal patch, including the Higuchi, first order, zero-order, Peppas, and Korsenmeyer models (Sachin et al., 2019).

Skin Irritancy Test

In order to assess potential skin irritation resulting from transdermal preparations, a 24-hour patch application is conducted on shaven rat skin. Any potential alterations to erythema and edema are recorded.

Prominent Transdermal Patches Applied in Various Health Issues

Innovative Transdermal Patches in Cancer Therapy

Research is also exploring the use of transdermal estrogen in treating metastatic prostate cancer, as well as fentanyl, buprenorphine, and morphine patches for alleviating cancer-related pain. Additionally, granisetron and other antiemetic patches are being investigated to reduce nausea and vomiting induced by chemotherapy. Other studies include pilot trials that focus on optimal patch placement sites on the body to evaluate the consistency of transdermal delivery. These studies also examine the effectiveness of methylphenidate patches in managing cancer-related fatigue and the potential benefits of adding nitroglycerin patches to chemotherapy and radiation therapy for enhancing progression-free survival in patients with metastatic non-squamous non-small-cell lung cancer (NSCLC) and rectal cancer (Ahn, 2017).

Cerebral Conditions and Disorders

 Clinical trials are exploring various patch-based add-ons for mental disorders, such as oestradiol patches, which may affect schizophrenia progression due to their impact on estrogen levels, and nicotine transdermal patches. Additionally, research into the selegiline transdermal patch (STP—Emsam) has been prompted by cognitive decline associated with HIV. Numerous studies have also investigated the use of patches in combination with antipsychotic medications (Fischer, 2019).

Management Strategies for Alzheimer's Disease

Studies evaluating the tolerability, safety, and efficacy of rivastigmine (Exelon) patches in dosages of 4.6, 9.5, and 13.3 mg/24 hours have shown improvements in cognition, assistance with activities of daily living (ADLs) for patients with severe Alzheimer's disease (AD), and enhanced overall functioning, while also reducing nausea and vomiting. These results highlighted the greater effectiveness of the higher-dose rivastigmine patch in managing severe AD, leading to its subsequent approval (Lee, 2018).