Binary lipid system-based granules with undissolved drug crystals enhance oral bioavailability by preventing degradation and improving permeability.

Olmesartan Medoxomil (OLM) is a prodrug of an angiotensin II receptor antagonist and a P-glycoprotein (P-gp) substrate that is converted into Olmesartan by esterases, resulting in low oral bioavailability (26%). The aim of the present study was to formulate Olmesartan Medoxomil liposomes by thin film hydration method using Vitamin E TPGS (P gp inhibitor). Initial screening of excipients was conducted using the One Factor At A Time (OFAT) approach, while optimization was performed using Box-Behnken Design (BBD). The drug-to-lipid ratio, the amount of cholesterol, and the surfactant were identified as independent variables, with vesicle size (nm) and entrapment efficiency (%) as dependent variables. Key process parameters were evaluated through OFAT analysis, and the formulation was optimized using BBD. The prepared liposomes were characterized through vesicle size (nm), zeta potential (mV), drug loading (%), Transmission Electron Microscopy (TEM), Differential Scanning Calorimetry (DSC), Fourier Transform Infrared Spectroscopy (FTIR), and Gas Chromatography (GC), followed by in vitro dissolution and in vivo pharmacokinetic study in 12 wistar rats. The vesicle size and entrapment efficiency of the optimized formulation were found to be 112.1nm and 98.88% respectively. In vitro drug release studies were conducted in the USP-II apparatus exhibited a biphasic release pattern compared to the marketed formulation Olmezest®10. In vivo pharmacokinetic studies in wistar rats showed a significant increase in oral bioavailability (3.23 times) of the liposomal formulation of Olmesartan Medoxomil (OLM-LIPO) in comparison to the marketed formulation Olmezest®10.

Spectrophotometric Estimation of Olmesartan Medoxomil and Metoprolol Succinate in Tablet Dosage Form by Zero Order Derivative and Area Under the Curve Method

A simple, sensitive and efficient ultra performance liquid chromatography-mass spectrometry (UPLC-MS/MS) method for simultaneous quantitative determination of olmesartan and hydrochlorothiazide in human plasma has been developed and validated. Using olmesartan-d4 and hydrochlorothiazide-13C-d2 as stable isotope-labeled internal standard (SIL-IS). Plasma samples were processed by protein precipitation. Separated on a ZORBAX Eclipse XDB-Phenyl column (150 mm × 4.6 mm, 5 μm) using a gradient elution with mobile phases methanol and 5 mM ammonium acetate. Detected by electrospray ionization (ESI) in negative ion mode of multiple reaction monitoring (MRM), mass transition ion pairs were m/z 445.1 → 149.0 for olmesartan, m/z 295.9 → 204.9 for hydrochlorothiazide, m/z 449.1 → 149.1 for olmesartan-d4, and m/z 301.0 → 272.0 for hydrochlorothiazide-13C-d2. Linear ranges were 10-2000 ng/mL for olmesartan and 1.5-300 ng/mL for hydrochlorothiazide. Mean recoveries of olmesartan, hydrochlorothiazide, olmesartan-d4, and hydrochlorothiazide-13C-d2 were 91.31%, 99.34%, 92.62%, and 98.61%, respectively. Our method was well validated in selectivity, carryover, lower limit of quantification (LLOQ), calibration curve, accuracy, precision, dilution effect, matrix effect (normal, hyperlipidemic, and hemolyzed matrices), stability, recovery, and IRS. It was successfully applied in a bioequivalence study of olmesartan medoxomil and hydrochlorothiazide tablets (20/12.5 mg) in healthy Chinese volunteers.

Abstract Olmesartan medoxomil (OLM), a widely prescribed antihypertensive agent, suffers from poor solubility and first pass metabolism, which lowers its bioavailability. This work aimed to develop novel cationic nanocarriers (LeciPlex) for OLM to enhance its dissolution and oral bioavailability. A central composite design (CCD) was employed to optimize OLM-loaded LeciPlex (OLM-LPX) formulations. The independent variables included lecithin amount, surfactant amount, and surfactant type. The influence of these factors on particle size (PS), entrapment efficiency (EE), surface charge (ZP), and cumulative in vitro drug release (CR) was thoroughly evaluated and examined. The optimized formulation underwent additional evaluation for ex vivo permeation, morphology, stability, in vivo histopathology, and pharmacokinetic studies. The optimized OLM-LPX exhibited desirable PS (149.23 ± 2.02 nm), ZP (+ 62.03 ± 2.45 mV), EE (82.25 ± 4.63%), and CR (88.87 ± 1.97% after 8 h), aligning well with the predicted CCD values. Ex vivo permeation of optimized OLM-LPX across rabbit intestine showed a cumulative OLM transport of 1973.1 ± 207.9 µg versus 909.9 ± 217.8 µg for OLM suspension, with a permeability coefficient 3.4-fold higher and a 2.17-fold increase in intestinal permeability. Transmission electron microscope images showed spherical-shaped and smooth particles. It also exhibited accepted stability over the predetermined storage period (90 days), showing neither sedimentation nor particle coalescence. The orally administered optimized OLM-LPX showed no evidence for inflammatory signs or mucosal damage within intestinal gut segments under histopathological examination. Pharmacokinetic evaluation in rats demonstrated that OLM-LPX achieved a C max of 3.48 ± 0.25 µg/mL versus 1.32 ± 0.21 µg/mL for suspension, extended t max (2 h vs. 1 h), and a markedly enhanced AUC ₀–∞ of 41.17 ± 3.41 µg·mL⁻¹·h compared to 11.48 ± 1.69 µg·mL⁻¹·h, corresponding to a relative bioavailability of 358.62%. Collectively, LPX may serve as an effective nanocarrier for effective oral administration of poorly soluble OLM, contributing to its enhanced bioavailability. Graphical Abstract

Multi-way calibration strategies involving excitation-emission data measurements from drug-modulated fluorescence in CdTe quantum dots and AgInS2 nanocrystals.

Critical review on the assessments of green metric tools for Olmesartan medoxomil analytical methods: Case studies

Background: The widespread implementation of unit-dose packaging has improved medication adherence, particularly in elderly populations. However, potential physicochemical interactions between co-packaged drugs remain a concern. Therefore, the present study evaluated the stability of metformin hydrochloride (MET) tablets and olmesartan medoxomil (OLMMD) tablets (orally disintegrating tablet: OLMOD/standard tablet: OLM), including both brand name and generic products, when unit-dose packaged and stored under a high temperature and humidity (40°C, 75% RH) or room temperature for up to 28 days. Methods: A visual inspection and HPLC quantification were used to assess the discoloration of MET and content of OLMMD. Results: When MET1 (brand name) or MET2 (generic) was packaged with OLMOD1 (brand name), no discoloration or degradation was observed. However, with MET3 (generic), time-dependent pink discoloration occurred when co-packaged with OLMOD2 or OLMOD3 (generics). OLMMD content remained nearly 100% even in formulations inducing MET discoloration. Differences were attributed to excipient and manufacturing variability. Notably, OLMOD1 uniquely contained β-cyclodextrin, which may stabilize OLMMD via inclusion complexation. By contrast, MET discoloration may reflect hygroscopicity and variability in film-coating properties. Although pharmacological efficacy was unaffected due to preserved OLMMD stability and the harmless nature of MET discoloration, visual changes may reduce patient adherence. Thus, selecting stable combinations that avoid discoloration is important in clinical practice, especially for elderly or cognitively impaired patients.Conclusions: This study highlights the importance of excipient selection and formulation design in ensuring stability in unit-dose packaging. The development of compatibility guidelines and formulation reference lists is warranted to support safe co-packaging practices.

Olmesartan medoxomil (OMN), a highly selective antihypertensive agent but, with problematic oral delivery due to its low solubility and limited bioavailability. Therefore, biomimetic lipid-based niosomes were adopted as a novel approach to enhance OMN solubility and boost its transdermal delivery (TD). Initially, conventional niosomes were prepared by thin film hydration method. Formulation parameters were adjusted to obtain entrapment efficiency (EE > 75%), particle size (PS < 300nm), zeta potential (ZP > ± 25 mV), and polydispersity index (PDI < 0.5). Based on these parameters, OMN-Ns-3 was selected for further modulation. Concomitantly, screening studies of OMN in 9 liquid lipids; clove oil, Maisine® CC, Transcutol® HP, castor oil, olive oil, Miglyol® 812, soybean oil, sesame oil, and cottonseed oil were performed. Among them, the first three showed the highest solubility of OMN; ~16.30 ± 1.80, 25.60 ± 2.20, and 38.35 ± 1.30mg/mL, respectively. Hence, they were incorporated into OMN-Ns-3 to obtain the modulated niosomal formulation; M/C-OMN-Ns-T. It showed accepted EE 98.70 ± 1.40%, PS 186.30 ± 2.40nm, ZP -36.20 ± 0.70 mV, and PDI 0.34 ± 0.03. It showed enhanced cumulative amount of OMN permeated; Q24 93.72 ± 0.49%, Q48 97.56 ± 0.66%, and Q72 98.22 ± 1.15%. Ex vivo studies showed significantly enhanced flux (Jmax) compared to conventional niosomes with enhancement ratio values ~ 1.6 at 24/48h, and 1.5 at 72h (p < 0.0001). Confocal Laser Scanning Microscopy showed vast distribution and deep localization of fluorescent M/C-OMN-Ns-T, creating in-skin depot for sustained OMN diffusion to the systemic circulation. TEM images showed nanosized, non-aggregated spherical vesicles. Physical stability studies showed no significant changes in EE, PS, ZP, and PDI. M/C-OMN-Ns-T formulated into transdermal patch (TP) showed accepted physicochemical properties including; thickness, folding endurance, surface pH, drug content Q24, and Q48. In vivo pharmacokinetic studies of TP showed significantly enhanced relative bioavailability ~ 674.04% compared to angiosartan oral tablets (p < 0.0001). It could be concluded that TD of M/C-OMN-Ns-T reflected its superiority over conventional lipid-free niosomes. Our study introduced the potential of liquid lipids as biomimetic fluidizing agents for enhanced TD of conventional nanocarriers. The developed TP could be a competent alternative to conventional oral delivery of OMN.

Background/Objectives: Fixed-dose combination (FDC) antihypertensive medications containing olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide are widely used for the treatment of essential hypertension. Although effective, the use of racemic amlodipine, which contains both active S(−)-amlodipine and inactive R(+)-amlodipine, has been associated with dose-dependent adverse effects, such as peripheral edema. S-amlodipine, a pharmacologically active enantiomer, provides comparable antihypertensive efficacy at half the dose with a lower incidence of side effects. Methods: In this study, a modified FDC formulation was developed by replacing racemic amlodipine with S-amlodipine to enhance tolerability while maintaining therapeutic efficacy. Results: A bilayer tablet design was employed to minimize the formation of impurities and ensure formulation stability, which was confirmed under stress and accelerated conditions. In vitro dissolution testing demonstrated pharmaceutical equivalence with the marketed reference FDC, and an in vivo pharmacokinetic study confirmed bioequivalence. Conclusions: These results suggest that the newly developed S-amlodipine besylate-containing FDC tablet is a viable alternative to existing olmesartan/amlodipine/hydrochlorothiazide combinations, offering comparable efficacy and pharmacokinetic properties with the potential for improved safety and patient adherence in the management of hypertension.

Background/Objectives: Prodrug strategies are a vital aspect of drug development, with ester prodrugs particularly notable for modifying parent drug properties through ester functional groups to enhance oral absorption. However, ester prodrugs are prone to hydrolysis by water and enzymes, making stability in the gastrointestinal (GI) tract prior to absorption a key challenge. Few formulation strategies effectively address this degradation issue. We recently introduced binary lipid systems (BLS), comprising a lipid and a water-soluble surfactant only that form stable microemulsions. This study aimed to explore the application of BLS for enhancing the oral absorption of ester prodrugs by coating drug crystals with BLS in solid granules and study the impact of the compositions of BLS on oral absorption. Methods: Olmesartan medoxomil (OLM), a methyl ester prodrug of olmesartan (OL), was selected as a model drug. Various lipids were combined with TPGS to form BLS and used to prepare OLM solid granules containing OLM crystals. Results: Among the tested formulations, OLM MCM-TPGS granules significantly enhanced drug release and protected OLM from enzyme-mediated degradation in two-step dissolution studies with esterase. Pharmacokinetic and tissue distribution studies in rats confirmed that OLM MCM-TPGS granules improved oral absorption by 145% and increased tissue uptake compared to OLM powder. Conclusions: This approach overcomes solubility limitations when using lipids and surfactants as excipients, enabling high drug loading in solid dosage forms and expanding the utility of lipids and surfactants for water-insoluble drugs. This novel formulation strategy holds great potential for enhancing oral absorption of ester prodrugs, representing a significant advancement in formulation technologies and offering more effective and versatile drug delivery solutions.

The Need, Quality, and Sustainability (NQS) index was very recently developed. It evaluates the compromise of analytical techniques between social needs, analytical performance, and global sustainability. Regarding ARBs, Olmesartan (OLM) has become one of the worldwide first-line antihypertensive therapies. Its fixed-dose combinations present a solution for insufficient monotherapy or comorbidity conditions. Thus, the demand increased to develop methods that could analyze OLM fixed-dose combinations. This work has adopted the second derivative spectrofluorimetry for assaying OLM with either the β-blocker (Metoprolol, MET) or the cholesterol-lowering drug (Atorvastatin, ATR) in their combined tablets. Comparative sustainability assessment of the proposed versus the reported ones was achieved using the most modern tool (NQS index). For the first time, it was calculated based on whiteness R3GB 12 model as "Quality" aspect. It employs an innovative efficient relative ranking approach using a simple Microsoft Excel function. In addition, the green solvent selection tool (GSST) was incorporated in selecting the greener extraction solvent. Comprehensive evaluation of the reported methods highlights the advantages of the proposed analytical approach. Implementing them in routine analysis of the studied OLM binary combinations was encouraged by high selectivity, linearity, eco-friendliness, and simplicity. Being economic potentiates their vast application in developing countries.

Method Development and Validation of Olmesartan Medoxomil by Using RP-HPLC

The antihypertensive medication olmesartan medoxomil (OLM) is pharmacologically selective angiotensin-II receptor antagonist. Pharmaceutically speaking, OLM is a class II medication (low solubility, high permeability) that is practically insoluble.Due to its extremely poor solubility, which negatively affects its usefulness, oral medication have a low (26%) bioavailability. The current strategy involves generating OLM as a micellar dispersion in the nano range scale utilizing the film hydration process. In order to prepare transparent aqueous formulations, increase drug solubilization, and administer medication orally, Soluplus (SLP) was employed as a micellar nanocarrier.Different SLP concentrations were used to make eight formulations. Micelle size, polydispersity, morphology, encapsulation efficiency and in vitro release testing were used to gauge the micellar system's concentration-dependent characteristics. The systems' particle sizes ranged from 48.9 ±0.98 nm (F8) to 461.3± 5.07 nm (F1), with approved poly dispersity index values. OLM release behavior in vitro from micelles with particle size less than 100 nm against a pure medication aqueous suspension was evaluated. In comparison to pure drug powder suspension, all tested formulas demonstrated a significant increase in drug release at p˂0.05. The chosen formulation was subjected to lyophilization , fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC) analysis, transmission electron microscopy (TEM) observation ,stability and ex vivo permeation investigations utilizing the non everted intestinal sac technique. F7 with SLP concentration 1.6% showed higher percentage of drug release with particle size of 51.09 nm. DSC of lyophilized F7 formula showed absence of crystalline state which mean complete encapsulation of drug within nanocarrier .The FTIR revealed no incompatibility between drug and excipient. The results of particle size analysis were analogous to TEM image.The selected formula was stable upon storage and dilution with water.The ex vivo study showed improvement in the permeability of the formulated nanomicelle (NM) and the permeability coefficient was increased more than two time compared to the pure drug dispersion. Accordingly it deduced that formulating OLM-NM based on SLP is a promising strategy. It can improve OLM permeability by two and release.

The article presents a review of studies on the use of olmesartan medoxomil in hypertension. Most studies have shown that olmesartan medoxomil provides effective blood pressure control in patients with hypertension with a different cardiovascular risk profile with good tolerability. It was noted that olmesartan medoxomil has pleiotropic effects: vasoprotective, cardioprotective, nephroprotective, cerebroprotective, antiatherogenic, anti-inflammatory. The role of olmesartan medoxomil in the prevention (reduction of risk) of cognitive impairment or dementia has been established.

Olmesartan medoxomil (OLM) is an ester prodrug of olmesartan (OL) developed to overcome the poor permeability of OL. OLM is an angiotensin receptor blocker and is commonly used to treat hypertension. However, OLM has low water solubility and low bioavailability of 26%. It is understood that OLM is unstable in aqueous media; however, this hydrolysis has not been specifically studied in a way that has produced reliable, publishable data. Previously published analytical methods tend to focus mainly on quantitative measurement of OLM, but not quantitative measurement of OL. The objective of this study was to investigate the solubility and aqueous hydrolysis of OLM in different pH buffers by developing an analytical method for the simultaneous measurement of OLM and OL. A novel HPLC method was developed and validated to simultaneously quantify OLM and OL. The solubility of OLM was pH-dependent 37°C, which could lead to food effects and precipitation of OLM in the small intestine. The aqueous hydrolysis of OLM was rapid and significant and followed the zero-order kinetic model with different hydrolysis rates varying across different pH levels in the order: pH 1.2 < pH 3.5 < pH 4.6 ≈ pH 6. These findings indicate that, in addition to low water solubility, aqueous hydrolysis in the gastrointestinal tract contributes to OLM's low bioavailability. The study emphasizes the importance of fully understanding the solubility and hydrolysis of ester-based prodrugs. Strategies that protect OLM from hydrolysis could have the potential to enhance its bioavailability. Considering ester prodrugs are a key strategy to improve bioavailability, our study in this manuscript is significant for drug formulation development.

Drug discovery campaigns often face biopharmaceutical challenges, some of which can be solved by a prodrug approach. Prodrugs are enzymatically or chemically transformed in vivo to produce active drugs. Among these, medoxomil promoieties have been judiciously employed in multiple drug discovery campaigns, leading to three prodrugs gaining FDA approval: azilsartan medoxomil (6), olmesartan medoxomil (20), and ceftobiprole medocaril (29), and one approval in Japan: prulifloxacin (35). The promoiety can be easily appended to mask carboxylic acids, amines, zwitterionic compounds, and other polar groups, imparting lipophilicity to the parent compound. The promoiety has the added advantage of rapid and complete conversion to the parent drug by multiple enzymatic pathways across different tissues. The approach has been used for drugs spanning multiple classes to improve oral bioavailability, solubility, tissue localization, efflux, and side effect profiles. This Perspective analyzes the history and application of medoxomil prodrugs and discusses their potential for drug development.

Olmesartan Medoxomil (OLM), is a BCS Class II hypertension drugs, with low solubility in water, leading to limited bioavailability. This study aimed to increase the dissolution rate of OLM using a Solid-Self Micro Emulsifying Drug Delivery System (S-SMEDDS). In the beginning, oils, surfactants, and co-surfactants were assessed for drugs solubility. Liquid SMEDDS was created by combining Capmul MCM (30-50%) as oil with Gelucire 44/14 and Transcutol HP (50-70%) as surfactants and co-surfactants. The method was tested for % transmittance, cloud point, reconstitution ability, stability, and drug content. Optimized SMEDDS, made up of Gelucire 44/14 (46.5%), Capmul MCM (40%), and Transcutol HP (23.5%), had good emulsification characteristics, including an adequate zeta potential, particle size, and polydispersity index (PDI). It was then adsorbed onto Neusilin U2 to obtain S-SMEDDS, which was further characterized by Differential Scanning Calorimetry (DSC) that confirmed no drug-excipient interactions, while Scanning Electron Microscopy (SEM) verified successful adsorption of liquid SMEDDS. The S-SMEDDS was formulated into a fast-dissolving tablet (FDT) using suitable excipients, exhibiting good flow properties and a disintegration time of 108 seconds. In vitro dissolution studies revealed 90% drug release in 60 minutes, significantly higher than the 35.4% release observed with pure drug. These results suggest that the S-SMEDDS-based fast-dissolving tablet of OLM could act as a novel drug delivery system for increasing solubility and bioavailability, offering a more effective oral treatment for hypertension. Keywords: Olmesartan Medoximil, S-SMEDDS, Croscarmellose Sodium, Fast Disintegrating Tablet

This study aims to develop and validate a Ultra violet spectroscopic analytical method for accurately measuring Olmesartan Medoxomil (OLM), Telmisartan (TEL), and Valsartan (VAL), three common antihypertensive drugs. These medications block angiotensin II at the AT1 receptor, reducing blood pressure through vasodilation and decreased water retention. UV spectrophotometry offers a simple and cost-effective approach for drug quantification. The objective is to establish specific wavelengths for each drug and evaluate derivative and AUC techniques for precise measurement. A diluent of 0.1N sodium hydroxide and distilled water (3:7) was used, yielding wavelengths of 248 nm for OLM, 295 nm for TEL, and 250 nm for VAL in zero-order analysis. First-order derivative peaks were identified at 264 nm, 284 nm, and 267 nm, while second-order derivatives showed 252 nm, 241 nm, and 239 nm for OLM, TEL, and VAL, respectively. AUC analysis further refined ranges for each compound. The method was validated for accuracy, precision, sensitivity, and detection limits using this solvent system. Results demonstrated that the UV spectrophotometric method was effective for the precise quantification of OLM, TEL, and VAL. The common solvent system ensured efficiency in routine quality control. In pharmaceutical settings, this approach offers a dependable, rapid, and economical technique for monitoring these drugs.

Olmesartan medoxomil, classified as BCS class II due to its poor water solubility, exhibits a low oral bioavailability of 28.6%. Microballoons of Olmesartan medoxomil were formulated using the ionotropic gelation technique and subjected to various evaluation parameters. The particles were found to be in the range of 85.11 to 312.6 µm. The prepared microballoons remained buSSoyant for more than 12 hours and showed percentage of cumulative drug release between 56.32-83.62%. In vivo studies showed significant reduction in Systolic blood pressure (SBP) in optimized formulation (OF). The formulated microballoons (hollow microspheres) emerged as a promising option for an oral gastro retentive controlled drug delivery system for Olmesartan medoxomil.