ANALYTICAL METHOD DEVELOPMENT AND VALIDATION OF TERTIARY COMBINATIONS OF ANTIHYPERTENSIVE DRUGS: A REVIEW

ANALYTICAL METHOD DEVELOPMENT AND VALIDATION OF TERTIARY COMBINATIONS OF ANTIHYPERTENSIVE DRUGS: A REVIEW

Purva Patel and Hiral Dave *

Department of Pharmaceutical Quality Assurance, Parul Institute of Pharmacy, Parul University, P.O Limda, Vadodara, Gujarat, India.

ABSTRACT: The most important risk factor for cardiovascular disease is high blood pressure, which accounts for around one-third of those who have it. A majority of those who have hypertension are not on antihypertensive medication. It is not a disease, but it is an important risk factor for cardiovascular disease. Hypertension includes the intricate exchange of natural and pathophysiological factors that influence numerous frameworks, just as hereditary inclination. Investigation of patients with hypertension incorporates exact normalized blood pressure (BP) estimation, evaluating patients' anticipated danger of atherosclerotic cardiovascular disease, declaration of target organ harm, location of auxiliary reasons for hypertension, and presence of comorbidities, including cardiovascular disease kidney infection. As a part of many risk factor reduction activities, combination drug therapy is as a well-established option for cardiovascular disease risk reduction. Over the past couple of years, there has been much research done on antihypertensive drugs and there have been many patents that can be beneficial for research purposes. A key element of discovering new drugs, advancing new drugs and assembling pharmaceutical products is the development of analytical methods and their validation. Analytical methods should be used in the Good Manufacturing Practice and Good Laboratory Practice environments and must be developed using the protocol and acceptance criteria in the ICH Q2(R1) guidelines. The following literature surveys reveal that all methods were reported for all tertiary combinations. However, Ultraviolet spectrophotometry Reverse Phase High-Performance Liquid Chromatography, High-Performance Thin-Layer Liquid Chromatography, stability-indicating Reverse Phase High-Performance Liquid Chromatography methods.

Keywords: Analytical method, Hypertension, High-performance liquid chromatography, Liquid chromatography-mass chromatography, High-performance thin layer liquid chromatography, Patent search, Ultraviolet spectroscopy

INTRODUCTION: Anti-hypertensives drugs are used to treat hypertension (high blood pressure). People with hypertension are very commonly seen to suffer from this chronic condition.

Current hypertension treatment guidelines recommend a goal of <140/90 mmHg> for a population with uncomplicated hypertension, and goals are even <130/80mmHg> for patients with diabetes or renal disease.

According to the studies that have been conducted over the long term, the higher the blood pressure reduction, the lower the cardiovascular death risks. Major clinical studies have revealed that most patients require two or more drugs to reach their blood pressure goals.

Evidence suggests that lowering the blood pressure by 5mm Hg can decrease the risk of stroke by 34%, ischemic heart disease by 21% and reduce the likelihood of dementia, heart failure and mortality from cardiovascular disease ².

Combination therapy should be used as the initial treatment of patients whose probability of achieving monotherapy's BP control is low. As many risk factors as possible can be reduced by using combination drug therapy to reduce cardiovascular disease risk.

Type of Hypertension: There are two types of hypertension. Primary hypertension (Essential). Secondary hypertension.

Primary Hypertension: Primary hypertension is the most common type, affecting between 90-95% of patients diagnosed with essential hypertension. Primary hypertension does not have to be identified clearly. The majority of cases are of essential hypertension i.e., the cause is not known.

Sympathetic and renin-angiotensin systems may or may not be overactive, but they contribute to blood vessels' tone ³. In this case, hypertension greater than 130 systolic and 80 diastolic has occurred without any diagnosis or treatment.

There can be multiple risk factors contributing to primary hypertension, including excessive salt consumption, abnormalities involving the renin-angiotensin-aldosterone system, and pathogenic disturbances of the CNS such as stress.

Secondary Hypertension: It has been discovered that secondary hypertension causes 5% of all hypertension cases. A medical condition (such as kidney or liver malfunction) or medication can result in high blood pressure.

An abnormality in the arteries supplying blood to the kidneys is the most common cause of hypertension. Additionally, some people suffer from thyroid diseases, hormonal abnormalities, tumors of the adrenal glands, and airway obstructions during sleep if they consume too much salt or alcohol.

Pathophysiology of Hypertension: Hypertension results from irregular physiological regulation of blood pressure resulting from multiple mechanisms. The blood pressure is a product of cardiac output and systemic vascular resistance.

The blood pressure is determined by the interaction of multiple genetic, environmental and demographic factors that influence to hemodynamic variables shown in Fig. 1, cardiac output, and total peripheral resistance. Cardiac output is affected by the blood volume, itself greatly dependent on body sodium homeostasis ⁵.

As the blood vessels contract, humoral factors that cause vasoconstriction (such as angiotensin II) and vasodilators (prostaglandins and nitric oxide) are activated. Resistance vessels also exhibit autoregulation, whereby increased blood flow induced vasoconstriction to fight against tissue hyperperfusion.

Other local factors such as pH and hypoxia and neural interactions (α- and β- adrenergic systems) may be important ⁴. The kidneys play a significant role in blood pressure regulation, as follows:

• In the renin-angiotensin system, the kidney influence both peripheral and sodium hemostasis. The juxtaglomerular cells of the kidney produce renin to change plasma angiotensinogen into angiotensin I, which is then converted by angiotensin-converting enzyme (ACE) to angiotensin II ⁴.
• Angiotensin II increases peripheral resistance and blood volume simultaneously, shown as in 2.
• The kidneys also produce a vasodepressant that counterbalances angiotensin's effects as a vasodepressant.
• In response to volume expansion, heart atria secrete natriuretic factors independent of the glomerular filtration rate, which inhibit sodium reabsorption by distal tubules and cause vasodilation ⁴.
• When the renal excretory function is impaired, n creased atrial pressure is a compensatory mechanism to restore fluid and electrolyte balance ⁴.

FIG. 1: GENETIC INFLUENCE +ENVIRONMENT FACTOR RELEVANT TO HYPERTENSION

FIG. 2: RENIN ANGIOTENSIN ALDOSTERONE SYSTEM

Proposed Disease Treatment: Controlling and managing high blood pressure can be achieved by changing your lifestyle. In England and Wales, over seven million adults appear on the initial care hypertension registers, which is around 14% of the adult population ⁵. By lowering BP to an acceptable level with minimal patient inconvenience, antihypertensive therapy can help prevent morbidity and mortality associated with persistently raised BP. Control technology has an important role to play in this scenario. Currently, 60% of those on hypertensive enrol are controlled ⁶ and only 50% of those starting on a new antihypertensive remaining taking it after 6 months ⁷.

Lifestyle Change: Different forms of non-pharmacological treatment to lower blood pressure and prevent hypertension. The most effective interventions are weight loss ^{8, 9}, reduced Na⁺ intake ^{9, 10, 11}, increased potassium intake ^{12, 13}, increased physical activity ¹⁴, reduced consumption of alcohol ¹⁵ and diets like the Dietary Approaches to Stop Hypertension (DASH) diet that includes elements that have favourable effects on blood pressure. The DASH diet is especially successful when combined with other effective BP lowering interventions such as a reduced dietary sodium intake ¹⁶. A lifestyle change is the most effective method of implementing these interventions.

Pharmacological Interventions: Low-dose pharmacological therapy has also been shown to be impressive in lowering BP and preventing hypertension in three randomized controlled trials conducted in adults with high normal BP ^{17, 18}. The Brazilian multicenter PREVER-Prevention Trial compared treatment with the low-dose long-acting thiazide-like diuretic chlorthalidone in combination with the potassium-sparing agent amiloride with treatment with placebo ¹⁹. Amiloride and chlorthalidone both lower blood pressure and hypertension, including a reduction in left ventricular mass when combined with low dose chlorthalidone.

Management of Hypertension:

Initiation of Antihypertensive Drug Therapy: Importantly, though the diagnosis of hypertension has been confirmed at the 130/80 mm Hg threshold, most patients with stage 1 hypertension (∼69%) do not qualify for immediate drug therapy ²⁰. In first-line therapy for pharmacological treatment of patients with masked hypertension, prescription of drug therapy is four drug classes- thiazide diuretics, calcium antagonists, ACE inhibitors, and angiotensin receptor blockers unless there is comorbidity consideration favoring the use of different class of the drugs.

Combination Therapy: Guidelines from WHO, ISH, and BHS encourage single-drug therapy; however, a second (and third, or even fourth) drug may be prescribed when the primary therapy fails. The hypertension study found that 70% of patients who achieved target blood pressure took two or three drugs. In the management of hypertension, few studies have been conducted on how the different combinations perform. Table 1 shows a list of recommended and not recommended ²¹.

A combination of antihypertensive agents is a fixed dose or free combination, including a diuretic. These combinations have been shown to produce greater blood pressure reductions than those seen with monotherapies ²⁴. Combinations of a calcium antagonist with a renin-angiotensin system inhibitor (RASI), whether an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) ^{25, 26}, have also been shown to be effective and safe in the management of the hypertensive patient ^{25, 26}. Patients with left ventricular hypertrophy, who are taking ACE inhibitors/ARBs, benefit greatly from this combination.

TABLE: 1 RECOMMENDED AND NOT RECOMMENDED COMBINATIONS

Patent Search for Antihypertensive Drugs: Over the past couple of years, there has been much research done on antihypertensive drugs. There have been many patents that can be beneficial for research purposes. Table 2 shows a list of the patent search for antihypertensive drugs.

TABLE 2: PATENT SEARCH

Analytical Method Validation: The development and validation of analytical methods play a crucial role in developing, advancing, and assembling pharmaceutical products. An analysis of drug substances and drug products includes determining their purity and toxicity.

A method of developing analytical methods primarily employed in multicomponent analyses minimizes the time-consuming task of separating interferants and, therefore, reduces time and therefore costs, associated with the analysis of increasingly more analytes. The number of medications introduced to the market has increased in recent years. The steps of method development and validation depend upon type of method being developed; the following steps are common to most types of projects.

• Method development plan definition.
• Background information gathering.
• Laboratory method development.
• Generation to test procedure.
• Method validation protocol definition.
• Laboratory method validation.
• Validated test method generation.
• Validation report.

ICH Q2(R1) guidelines also mention that analyses must adhere to GMP and GLP practices; protocols and acceptance criteria must be followed when developing analytical methods ⁵⁴.

Development and validation of analytical methods play a critical role in pharmaceutical manufacturing and develop-pmentthe following literature surveys reveal there is all methods were reported for all tertiary combinations. However, UV spectro-photometry, RP- HPLC, HPTLC, and stability indicate RP-HPLC methods. The reported methods are shown in Table 3.

TABLE 3: REPORTED METHODS FOR ASSESSMENT OF TERTIARY COMBINATIONS

CONCLUSIONS: All tertiary combination drugs are shown to be more effective in this article. A literature review is presented to provide information on different methods for determining all combinations of tertiary drugs. Several patents have been published on antihypertensive drugs in the last two or three years that are helpful to researchers.

The different analytical methods are reported for the combinations like UV Spectroscopy, HPLC, LC-MS, HPTLC, stability-indicating, and RP-HPLC. Additionally, this article presents the pharmacological action and solubility of all tertiary combinations. This review will help develop the analytical method for these new combinations and gives the knowledge about the characteristics of all tertiary combination’s drugs.

ACKNOWLEDGEMENT: We wish to acknowledge the Department of Pharmaceutical Quality Assurance at Parul Institute of Pharmacy, Parul University, for his help and support in the compilation of the article.

CONFLICTS OF INTEREST: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

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    How to cite this article:

    Patel P and Dave H: Analytical method development and validation of tertiary combinations of antihypertensive drugs: a review. Int J Pharm Sci & Res 2022; 13(9): 3447-57. doi: 10.13040/IJPSR.0975-8232.13(9).3447-57.

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