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Drug Development and Industrial Pharmacy Aug 2019Olmesartan medoxomil (OM) is a hydrophobic antihypertensive drug with low bioavailability (26%) and is known to have adverse effects such as celiac disease and...
Olmesartan medoxomil (OM) is a hydrophobic antihypertensive drug with low bioavailability (26%) and is known to have adverse effects such as celiac disease and enteropathy. The purpose of this study was to develop SMEDDS to increase bioavailability and decrease potential side effects of OM. Hydrophilic lipophilic balance was calculated by testing solubility of OM in different oils, surfactants, and cosurfactants to obtain the most suitable combination of SMEDDS. Pseudoternary phase diagram was used to select the better oil/water formulation of SMEDDS. After a test for 3-month stability, dissolution tests and parallel artificial membrane permeability assay (PAMPA) were conducted to investigate drug solubility and permeability. Biodistribution of fluorescent marked SMEDDS was observed by using imaging system. The pharmacodynamics of the drug were determined by measuring blood pressure from tails of rats. At the end of the experiment, intestines were examined for adverse effects of OM. Compared with tablet formulation according to the dissolution study, SMEDDS formulation showed 1.67 times improvement in solubility of OM. PAMPA studies suggested a much faster permeability rate for OM SMEDDS compared to the suspension form. Labeled SMEDDS gave 3.96 times stronger fluorescent emission than control dye administered mice in imaging system (IVIS) studies, indicating an increased bioavailability. Treating effect of SMEDDS was 3.1 times more efficient compared to suspension in hypertensive rats. It caused neither celiac-like enteropathy nor diarrhea, during 21-day noninvasive blood pressure system (NIBP) assay. Our results suggest that SMEEDS formulation improves dissolution and oral bioavailability of OM while reducing its adverse effects.
Topics: Administration, Oral; Animals; Biological Availability; Chemistry, Pharmaceutical; Drug Delivery Systems; Emulsions; Hydrophobic and Hydrophilic Interactions; Male; Mice; Oils; Olmesartan Medoxomil; Particle Size; Rats; Rats, Wistar; Solubility; Surface-Active Agents; Suspensions; Tablets; Tissue Distribution
PubMed: 30986085
DOI: 10.1080/03639045.2019.1607868 -
Drug Development and Industrial Pharmacy Apr 2017Olmesartan medoxomil (OLM) is an antihypertensive drug with low oral bioavailability (28%) resulting from poor aqueous solubility, presystemic metabolism and...
OBJECTIVE
Olmesartan medoxomil (OLM) is an antihypertensive drug with low oral bioavailability (28%) resulting from poor aqueous solubility, presystemic metabolism and P-glycoprotein mediated efflux. The present investigation studies the role of lipid nanocarriers in enhancing the OLM bioavailability through oral delivery.
MATERIALS AND METHODS
Solid lipid nanoparticles (SLN) were prepared by solvent emulsion-evaporation method. Statistical tools like regression analysis and Pareto charts were used to detect the important factors effecting the formulations. Formulation and process parameters were then optimized using mean effect plot and contour plots. The formulations were characterized for particle size, size distribution, surface charge, percentage of drug entrapped in nanoparticles, drug-excipients interactions, powder X-ray diffraction analysis and drug release in vitro.
RESULTS AND DISCUSSION
The optimized formulation comprised glyceryl monostearate, soya phosphatidylcholine and Tween 80 as lipid, co-emulsifier and surfactant, respectively, with an average particle size of 100 nm, PDI 0.291, zeta potential of -23.4 mV and 78% entrapment efficiency. Pharmacokinetic evaluation in male Sprague Dawley rats revealed 2.32-fold enhancement in relative bioavailability of drug from SLN when compared to that of OLM plain drug on oral administration.
CONCLUSION
In conclusion, SLN show promising approaches as a vehicle for oral delivery of drugs like OLM.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Administration, Oral; Animals; Antihypertensive Agents; Biological Availability; Chemistry, Pharmaceutical; Drug Carriers; Drug Stability; Emulsions; Excipients; Lipids; Male; Nanoparticles; Olmesartan Medoxomil; Particle Size; Rats; Rats, Sprague-Dawley; Solubility; Surface-Active Agents
PubMed: 28005442
DOI: 10.1080/03639045.2016.1275666 -
AAPS PharmSciTech Dec 2018Olmesartan medoxomil (Olm) and hydrochlorothiazide (HCTZ) are fixed dose combination (FDC) for treatment of hypertension. They have hydrogen bonding sites and may...
Olmesartan medoxomil (Olm) and hydrochlorothiazide (HCTZ) are fixed dose combination (FDC) for treatment of hypertension. They have hydrogen bonding sites and may interact during co-processing. The consequences of such interaction are not clear. This study investigated the possibility of this interaction during co-processing. The research was extended to inhibit deleterious interactions. The drugs were co-evaporated from ethanolic solution to maximize the chance of interaction. This was performed in the absence and presence of hydroxypropyl methylcellulose (HPMC) and/or aerosil. The products were characterized using Fourier transform infrared spectroscopy (FTIR), differential thermal analysis, and powder X-ray diffraction (PXRD) in addition to dissolution studies. Co-evaporation of Olm with HCTZ in the absence of excipients produced crystalline material with FTIR spectrum showing intermolecular hydrogen bonding. This material showed thermal pattern of new crystalline species. This was identified as Olm/HCTZ co-crystal by PXRD. This co-crystallization reduced the dissolution rate of both drugs. This co-crystallization was inhibited in the presence of HPMC, but the dissolution rate was not significantly enhanced accordingly. Co-processing in the presence of both HPMC and aerosil eliminated the co-crystallization and minimized the intermolecular drug-drug interaction with subsequent dissolution enhancement. The study introduced a composition for fixed dose combination of Olm and HCTZ with enhanced dissolution.
Topics: Antihypertensive Agents; Crystallization; Drug Combinations; Hydrochlorothiazide; Olmesartan Medoxomil; Solubility
PubMed: 30560314
DOI: 10.1208/s12249-018-1207-9 -
High Blood Pressure & Cardiovascular... Sep 2017Poor adherence to antihypertensive treatment is the single most important factor of unsatisfactory blood pressure (BP) control. This review focuses on therapy-related... (Review)
Review
Poor adherence to antihypertensive treatment is the single most important factor of unsatisfactory blood pressure (BP) control. This review focuses on therapy-related factors affecting adherence and suggests how to improve it with a wise choice of treatment schedule. Complex drug treatment schemes, poor tolerability and drug substitutions are frequent causes of poor adherence which, in turn, causes insufficient BP control, greater incidence of cardiovascular events and, finally, higher global health costs. The effects of prescribing generic drugs and of drug substitutions on adherence is also discussed. In terms of adherence, generic drugs do not seem to be better than branded drugs, unless patients have to bear very high "out of pocket" expenses to buy original drugs, suggesting no advantages in switching drug with the mere goal of reducing the cost of therapy. An important role in improving adherence (and thus cardiovascular events and health expenditure) is also played by the availability of fixed-dose combinations; among antihypertensive drugs, angiotensin receptor blockers (ARBs) are those associated with higher levels of adherence and persistence. Among ARBs, olmesartan stands out for a wide choice of effective fixed-dose combinations.
Topics: Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Blood Pressure; Cost Savings; Cost-Benefit Analysis; Drug Costs; Drug Substitution; Drug Therapy, Combination; Drugs, Generic; Humans; Hypertension; Imidazoles; Medication Adherence; Olmesartan Medoxomil; Tetrazoles; Time Factors; Treatment Outcome
PubMed: 28695464
DOI: 10.1007/s40292-017-0221-4 -
Journal of the... Dec 2015The pathophysiological role of oxidative stress (OxSt) in hypertension and target organ damage is recognized. Angiotensin II (Ang II) induces OxSt via NAD(P)H oxidase...
The blocking of angiotensin II type 1 receptor and RhoA/Rho kinase activity in hypertensive patients: Effect of olmesartan medoxomil and implication with cardiovascular-renal remodeling.
HYPOTHESIS/INTRODUCTION
The pathophysiological role of oxidative stress (OxSt) in hypertension and target organ damage is recognized. Angiotensin II (Ang II) induces OxSt via NAD(P)H oxidase activation and production of proinflammatory cytokines/growth factors leading to cardiovascular-renal remodeling. Ang II stimulates the RhoA/Rho kinase (ROCK) pathway, which is deeply involved in the development of cardiovascular-renal remodeling via OxSt induction. Olmesartan, an Ang II type 1 receptor blocker, possesses antioxidant and activating nitric oxide system-related effects, which we have shown in terms of p22(phox) reduction, heme oxygenase-1 and calcitonin gene-related peptide increase. This study evaluates in 15 untreated hypertensive patients the effect of olmesartan treatment on p63RhoGEF, key in Ang II-induced ROCK activation, and MYPT-1 phosphorylation, a marker of ROCK activity.
MATERIALS AND METHODS
The p63RhoGEF protein level and MYPT-1 phosphorylation (Western blot) were evaluated at baseline, and after three and six months of olmesartan treatment.
RESULTS
Olmesartan normalized systolic and diastolic BP (p < 0.001), reduced p63RhoGEF level: 1.3±0.25 d.u. (baseline) vs 1.0±0.29 (three months), p < 0.0001 vs 1.0±0.22, (six months), p < 0.0001 and MYPT-1 phosphorylation: 1.2 ±0.14 (baseline) vs 0.9±0.19 (three months), p = 0.008, vs 0.8±0.16 (six months), p = 0.001.
CONCLUSIONS
These data added to our previous results further provide a mechanistic rationale for olmesartan's antioxidant/anti-inflammatory potential translation, in the long term, toward anti-atherosclerotic/anti-remodeling effects reported by clinical trials.
Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Blood Pressure; Cardiovascular System; Densitometry; Diastole; Female; Humans; Hypertension; Kidney; Male; Middle Aged; Myosin-Light-Chain Phosphatase; Olmesartan Medoxomil; Phosphorylation; Receptor, Angiotensin, Type 1; Rho Guanine Nucleotide Exchange Factors; Systole; rho-Associated Kinases; rhoA GTP-Binding Protein
PubMed: 26240115
DOI: 10.1177/1470320315594324 -
Colloids and Surfaces. B, Biointerfaces Jun 2017The current study explores the potential of nanostructured lipid carriers (NLCs) for oral bioavailability enhancement of olmesartan medoxomil (OLM) by systemic design...
The current study explores the potential of nanostructured lipid carriers (NLCs) for oral bioavailability enhancement of olmesartan medoxomil (OLM) by systemic design approach. OLM-NLC was successfully prepared with optimized process parameters (i.e. amount of liquid lipid, total amount of lipid, drug content and surfactant concentration) using the Box-Behnken design of experiments for different response parameters (i.e. particle size, Polydispersity index and entrapment efficiency). Further, optimized formulation was validated which depicted nano size, homogenous distribution with optimum entrapment efficiency. OLM-NLC was characterized by different techniques viz. differential scanning calorimetry (DSC), powder X-Ray diffraction (PXRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM), which showed reduced crystallinity of the drug with smooth spherical appearance of nanoparticles. Formulation was found to be stable in simulated gastric fluids as no significant changes were found in size, PDI and entrapment efficiency. In vitro release showed extended release of OLM from OLM-NLC. In vitro cellular uptake study revealed 5.2 folds higher uptake of nanoparticles as compare to the free drug, when incubated with Caco-2 cells. In vivo performance showed that AUC and C of OLM-NLC were found significantly (P<0.01) higher as compare to the free drug. Overall, the present study successfully reports the improvement of oral bioavailability of olmesartan medoxomil.
Topics: Administration, Oral; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Biological Availability; Caco-2 Cells; Delayed-Action Preparations; Drug Carriers; Drug Stability; Gastric Juice; Humans; In Vitro Techniques; Lipids; Materials Testing; Nanoparticles; Olmesartan Medoxomil; Particle Size; Surface-Active Agents
PubMed: 28284054
DOI: 10.1016/j.colsurfb.2017.03.006 -
International Journal of Pharmaceutics May 2016Olmesartan is a hydrophobic antihypertensive drug with a short biological half-life, and low bioavailability, presents a challenge with respect to its oral... (Comparative Study)
Comparative Study
Design, formulation and optimization of novel soft nano-carriers for transdermal olmesartan medoxomil delivery: In vitro characterization and in vivo pharmacokinetic assessment.
Olmesartan is a hydrophobic antihypertensive drug with a short biological half-life, and low bioavailability, presents a challenge with respect to its oral administration. The objective of the work was to formulate, optimize and evaluate the transdermal potential of novel vesicular nano-invasomes, containing above anti-hypertensive agent. To achieve the above purpose, soft carriers (viz. nano-invasomes) of olmesartan with β-citronellene as potential permeation enhancer were developed and optimized using Box-Behnken design. The physicochemical characteristics e.g., vesicle size, shape, entrapment efficiency and skin permeability of the nano-invasomes formulations were evaluated. The optimized formulation was further evaluated for in vitro drug release, confocal microscopy and in vivo pharmacokinetic study. The optimum nano-invasomes formulation showed vesicles size of 83.35±3.25nm, entrapment efficiency of 65.21±2.25% and transdermal flux of 32.78±0.703 (μg/cm(2)/h) which were found in agreement with the predicted value generated by Box-Behnken design. Confocal laser microscopy of rat skin showed that optimized formulation was eventually distributed and permeated deep into the skin. The pharmacokinetic study presented that transdermal nano-invasomes formulation showed 1.15 times improvement in bioavailability of olmesartan with respect to the control formulation in Wistar rats. It was concluded that the response surfaces estimated by Design Expert(®) illustrated obvious relationship between formulation factors and response variables and nano-invasomes were found to be a proficient carrier system for transdermal delivery of olmesartan.
Topics: Administration, Cutaneous; Animals; Antihypertensive Agents; Biological Availability; Chemistry, Pharmaceutical; Drug Carriers; Drug Compounding; Drug Delivery Systems; Drug Liberation; Half-Life; Microscopy, Confocal; Monoterpenes; Nanoparticles; Olmesartan Medoxomil; Particle Size; Permeability; Rats; Rats, Wistar; Skin; Skin Absorption
PubMed: 27005906
DOI: 10.1016/j.ijpharm.2016.03.030 -
Journal of Hypertension Apr 2016Angiotensin receptor blockers (ARBs) are preferred antihypertensive therapies in patients with type 2 diabetes mellitus (T2DM). Azilsartan medoxomil (AZL-M) is a potent... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Angiotensin receptor blockers (ARBs) are preferred antihypertensive therapies in patients with type 2 diabetes mellitus (T2DM). Azilsartan medoxomil (AZL-M) is a potent ARB for the treatment of stages 1-2 hypertension. We compared the efficacy, safety, and metabolic effects of AZL-M to both valsartan (VAL) and olmesartan (OLM), separately in patients with impaired fasting glucose (prediabetes mellitus) and T2DM.
METHODS
A pooled analysis of 3821 patients from three separate randomized placebo-controlled trials comparing the effects of AZL-M (40 and 80 mg), OLM (40 mg), VAL (320 mg), and placebo on changes in ambulatory and clinic blood pressure (BP) among patients with hypertension and prediabetes mellitus or T2DM was performed. Two analysis pools were created to facilitate comparisons: Pool A included patients who received placebo, AZL-M or OLM and Pool B included those who received AZL-M or VAL. Within each pool, patients were stratified by glycemic subgroups (normoglycemic, prediabetes mellitus, or T2DM) based on hemoglobin A1c values. Changes from baseline in both 24-h and clinic SBP were the primary efficacy assessments.
RESULTS
Baseline 24-h mean SBPs were approximately 145 and 146 mmHg in the prediabetes mellitus and T2DM subgroups, respectively; corresponding clinic SBPs were approximately 158 and 159 mmHg. Baseline hemoglobin A1c values for each subgroup (both pools) were normoglycemic, 5.3%; prediabetes mellitus, 6.0%; and T2DM, 6.9%. Changes from baseline in 24-h or clinic SBP were significantly greater with AZL-M, 80 mg compared with either OLM 40 mg or VAL 320 mg in all subgroups in each pool. Safety and tolerability were similar among the active treatment and placebo subgroups.
CONCLUSION
These analyses indicate that AZL-M, 80 mg/day lowers SBP by a greater magnitude than OLM or VAL at maximally approved doses in patients with prediabetes mellitus and T2DM. These findings have important clinical implications for this high-risk patient group.
Topics: Adult; Aged; Antihypertensive Agents; Benzimidazoles; Blood Pressure; Diabetes Mellitus, Type 2; Female; Humans; Imidazoles; Male; Middle Aged; Oxadiazoles; Prediabetic State; Tetrazoles; Valsartan
PubMed: 26766564
DOI: 10.1097/HJH.0000000000000839 -
High Blood Pressure & Cardiovascular... May 2021Essential hypertension is the most common cardiovascular (CV) risk factor, being primarily involved in the pathogenesis of CV disease and mortality worldwide. Given the... (Review)
Review
Essential hypertension is the most common cardiovascular (CV) risk factor, being primarily involved in the pathogenesis of CV disease and mortality worldwide. Given the high prevalence and growing incidence of this clinical condition in the general population in both high and low-income countries, antihypertensive drug therapies are frequently prescribed in different hypertension-related CV diseases and comorbidities. Among these conditions, evidence are available demonstrating the clinical benefits of lowering blood pressure (BP) levels, particularly in those hypertensive patients at high or very high CV risk profile. Preliminary studies, performed during the Sars-COVID-19 epidemic, raised some concerns on the potential implication of hypertension and antihypertensive medications in the susceptibility of having severe pneumonia, particularly with regard to the use of drugs inhibiting the renin-angiotensin system (RAS), including angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). These hypotheses were not confirmed by subsequent studies, which independently and systematically demonstrated no clinical harm of these drugs also in patients with Sars-COVID-19 infection. The aim of this narrative review is to critically discuss the available evidence supporting the use of antihypertensive therapies based RAS blocking agents in hypertensive patients with different CV risk profile and with additional clinical conditions or comorbidities, including Sars-COVID-19 infection, with a particular focus on single-pill combination therapies based on olmesartan medoxomil.
Topics: Angiotensin Receptor Antagonists; Antihypertensive Agents; COVID-19; Comorbidity; Humans; Hypertension; Olmesartan Medoxomil; Pandemics; Pneumonia, Viral; Renin-Angiotensin System; SARS-CoV-2
PubMed: 33710599
DOI: 10.1007/s40292-021-00443-z -
International Journal of Nanomedicine 2019Olmesartan medoxomil (OLM) is an antihypertensive drug with low oral bioavailability due to extensive first-pass metabolism. This study aimed to prepare transetho somes...
INTRODUCTION AND AIM
Olmesartan medoxomil (OLM) is an antihypertensive drug with low oral bioavailability due to extensive first-pass metabolism. This study aimed to prepare transetho somes (TEs) for enhancing the transdermal delivery of OLM to avoid its oral problems.
METHODS
TE formulae were prepared utilizing 51.31 full factorial design using various surfactants (SAAs) and different phospholipid-to-SAA ratios. The formulae were characterized regarding their entrapment efficiency percentage (EE%), particle size (PS), polydispersity index (PDI), zeta potential (ZP), and the amount of drug released after 6 hours (Q6h). Design Expert software was employed to select the optimum formula.
RESULTS
The optimum formula (TE14) had an EE% of 58.50%±1.30%, PS of 222.60±2.50 nm, PDI of 0.11±0.06, ZP of -20.80±0.30 mV, and Q6h of 67.40%±0.20%. In addition, TE14 was compared to transferosomes (TFs) in terms of elasticity and was found to show higher deformability index. Further, evaluation of ex vivo permeation using both rat and shed snake skin showed higher permeability of TE14 compared to TFs and OLM suspension. Confocal laser scanning microscopy confirmed the capability of the fluorolabeled TE14 to penetrate deep within the skin, while the histopathological study confirmed its safety. TE14 successfully maintained normal blood pressure values of rats up to 24 hours. Moreover, TE14 showed superiority in dermatokinetic study when compared with drug suspension.
CONCLUSION
Taken together, the obtained results confirmed the potential of employing TEs as a successful carrier for the transdermal delivery of OLM.
Topics: Administration, Cutaneous; Animals; Antihypertensive Agents; Blood Pressure; Calorimetry, Differential Scanning; Drug Delivery Systems; Drug Stability; Elasticity; Factor Analysis, Statistical; Liposomes; Male; Methylprednisolone; Olmesartan Medoxomil; Rats, Wistar; Skin; Snakes
PubMed: 30936696
DOI: 10.2147/IJN.S196771