Formulation and Evaluation of Olmesartan Medoxomil Tablets

This work proposes a methodology for the design, development, and characterization of tablets prepared by the direct compression method of olmesartan medoxomil. The main objective was to ensure a high dissolution rate of the active ingredient. Therefore, a rigorous selection of excipients was carried out to ensure their physical and chemical compatibility with the active ingredient by scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FT-IR) studies. The suitability of the mixture for use in direct compression was performed using SeDeM methodology. The tablets met pharmacopoeia specifications for content uniformity, breaking strength, friability, and disintegration time.

Introduction

High blood pressure, along with smoking, hypercholesterolemia and hyperglycemia, are some of the major risk factors contributing to the increase in global morbidity and mortality from cardiovascular disease [1,2]. In turn, poorly controlled hypertension is the number one risk factor for cerebrovascular disease [3]. Hypertension is defined as an increase in systolic (SBP) and diastolic (DBP) blood pressure levels considered normal (SBP > 120 mmHg and DBP > 80 mmHg) [4].

Treatment is aimed at reducing morbidity and mortality rates associated with hypertension, starting with lifestyle modifications (smoking cessation, weight reduction, reduction of salt and alcohol intake, physical exercise) in combination with antihypertensive drugs [4]. The 2018 European guidelines recommend five main classes of antihypertensive drugs: angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin II receptor antagonists (ARA-II), β-adrenoblockers (BAB), calcium channel blockers (CCBs) and diuretics [5]. ARA-II or “sartans” potently and selectively block angiotensin II AT1 receptors resulting in vasodilation, decreased vasopressin secretion and aldosterone secretion [6,7]. ARA-IIs have demonstrated good tolerability, a high safety profile and antihypertensive efficacy with once-daily administration [8]. There are different types of ARA-IIs: olmesartan, losartan, valsartan, irbesartan and candesartan. In this research, olmesartan has been selected (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl-5-(2-hydroxypropane-2-yl)-2-propyl-3-[[4-[2-[2-(2H-tetrazol-5-yl) phenyl] methyl] imidazol-4-carboxylate), a high-intensity sartan that binds with higher affinity to the AT1 receptor than the other ARA-IIs, ensuring strong and persistent blockade of angiotensin actions [9].

Olmesartan medoxomil is an inactive prodrug that after oral administration is rapidly absorbed and undergoes rapid de-esterification through the gastrointestinal tract-giving rise to the active metabolite olmesartan [10]. Due to its low water solubility, it has a low oral bioavailability (approximately 26%), thus the Biopharmaceuticals Classification System (BCS) classifies olmesartan as class II (low solubility and high permeability) [11]. Drugs administered orally in tablet form have many advantages over other dosage forms, from good stability and easy manufacture to precise dosing that facilitates adherence to treatment [12]. Therefore, the main objective of this research is the design, development, and characterization of tablets prepared by direct compression of olmesartan medoxomil that provide a high dissolution rate of the active ingredient and thus increase its bioavailability.

The selection of tablets by the direct compression method is based on the advantages offered by this dosage form as well as the vision of subsequent industrial production as it is a simple and cost-effective manufacturing technology [13,14]. Consequently, the functionality and proportion of the excipients and the design of the production method are crucial in the compression process.

First, physical and chemical compatibility studies of olmesartan medoxomil and the selected excipients were performed by scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FT-IR), in order to select the most suitable excipients for the formulation design [15,16].

Secondly, the SeDeM galenic methodology was applied to the pre-formulation studies of direct compression tablets to obtain information on the active ingredient-excipient mixture in terms of its suitability for use in direct compression, thus allowing for faster formulation design [17,18].

Finally, a spectrophotometric analytical method was developed to identify from the correct mixing in the production process to the concentration of olmesartan medoxomil in the tablets.

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Materials

Olmesartan medoxomil (Insud Pharma, Madrid, Spain) (Figure 1), lactose monohydrate (Guinama, Valencia, Spain), microcrystalline cellulose (Vivapur 12®, JRS Pharma GmbH & CO.KG, Berlin, Germany), hypromellose (HPMC 2910), JRS Pharma GmbH & CO.KG, Berlin, Germany) and magnesium stearate (Guinama, Valencia, Spain).

González, R.; Peña, M.Á.; Torrado, G. Formulation and Evaluation of Olmesartan Medoxomil Tablets. Compounds 2022, 2, 334-352. https://doi.org/10.3390/compounds2040028

excipients formulation