Tailoring of PEGylated bilosomes for promoting the transdermal delivery of olmesartan medoxomil: in-vitro characterization, ex-vivo permeation and in-vivo assessment.

INTRODUCTION: The intention of this work was to load olmesartan medoxomil (OLM), a sparsely water soluble antihypertensive bioactive with low oral bioavailability (26%), into PEGylated bilosomes (PBs) for augmenting its transdermal delivery. PBs contain PEGylated single chain edge activator besides the components of traditional bilosomes (Span 60, cholesterol and bile salts). The PEG gives further resilience to vesicle membrane and is speculated to augment both permeability and bioavailability of OLM. METHODS: A 24 factorial experiment was constructed to inspect the impact of diverse variables on vesicles' features and sort out the optimal formula adopting Design Expert® software utilizing thin film hydration technique. Vesicles' evaluation was done by finding out entrapment efficiency percent (EE%), particle size (PS), polydispersity index (PDI), zeta potential (ZP) and amount of drug released after 6 hrs (Q6h). The optimal formula was selected and characterized for further investigations. RESULTS: The optimal formula (PB15) showed spherical vesicles with EE% of 72.49±0.38%, PS of 559.30±10.70 nm, PDI of 0.57±0.15, ZP of -38.35±0.65 mV and Q6h of 59.60±0.24%. PB15 showed higher deformability index (28.39±5.71 g) compared to traditional bilosomes (5.88±0.90 g) and transethosomes (14.94±0.63 g). Further, PB15 showed superior skin permeation from rat's skin relative to the drug suspension. Moreover, confocal laser scanning microscopy examination revealed efficient penetration of the fluoro-labeled PB15 through skin. Histopathological study ensured the safety of PB15. In addition, in-vivo skin deposition studies showed higher OLM deposition in rat's skin from PB15 compared to transethosomes and OLM suspension. Furthermore, pharmacodynamic and pharmacokinetic studies performed using male Wistar rats and male Albino rabbits, respectively, showed the superiority of PB15 over oral tablets. PB15 was found to have significantly higher AUC0-48 and AUC0-∞ relative to the oral tablets. As well, the relative bioavailability of PB15 was found to be 235.04%. CONCLUSION: Overall, the obtained results confirmed the creditable effect of PB15 for transdermal delivery.

Improving Adherence to Treatment and Reducing Economic Costs of Hypertension: The Role of Olmesartan-Based Treatment.

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.

Assessment of the Cardiovascular Risk of Olmesartan Medoxomil-Based Treatment: Meta-Analysis of Individual Patient Data.

INTRODUCTION: Results from two long-term studies (ROADMAP and ORIENT) indicated a numerical imbalance in the number of cardiovascular deaths between the olmesartan medoxomil (OM) and placebo groups. OBJECTIVE: Our objective was to conduct an individual patient data meta-analysis to provide more complete information regarding OM-associated cardiovascular risks and/or benefits. METHODS: We created an integrated database based on 191 clinical trials from the OM development program. Events were identified and adjudicated by an independent, blinded clinical events committee. The incidence of major cardiovascular events and total mortality for OM versus placebo/active control were evaluated, and the effect of OM on cardiovascular mortality (main endpoint of interest) and morbidity was calculated using a two-stage approach (Tian method). RESULTS: A total of 46 studies (~27,000 patients) met the US FDA-specified inclusion criteria (phase II-IV randomized, double-blind, placebo- or active-controlled studies [OM-based monotherapy or combination, double-blind period ≥28 days] and adult patients). The incidence of known adjudicated endpoints in the analysis of all studies combined was low among OM (0.11-0.53 %) and placebo/active control (0.08-0.76 %) groups. For cardiovascular mortality, the estimated risk difference (OM vs. control) was 0.00070 (95 % confidence interval [CI] -0.0011 to 0.0024; p = 0.60); the risk difference for each endpoint was <1/1000, with no statistically significant difference between groups. Results were similar with and without ROADMAP and ORIENT. DISCUSSION: The results from this meta-analysis did not show a clinically meaningful or statistically significant difference in cardiovascular risk between OM and the placebo/active control groups, and thus did not corroborate the numerical imbalance observed in ROADMAP and ORIENT.

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 ß-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.

Development and Validation of a Stability-Indicating Liquid Chromatographic Method for Estimating Olmesartan Medoxomil Using Quality by Design.

The current studies entail systematic quality by design (QbD)-based development of a simple, rapid, sensitive and cost-effective stability-indicating method for the estimation of olmesartan medoxomil. Quality target method profile was defined and critical analytical attributes (CAAs) for the reverse-phase liquid chromatography method earmarked. Chromatographic separation accomplished on a C18 column using acetonitrile and water (containing 0.1% orthophosphoric acid, pH 3.5) in 40 : 60 (v/v) as mobile phase at a flow rate of 1.0 mL/min with UV detection at 243 nm. Risk assessment studies and screening studies facilitated comprehensive understanding of the factors affecting CAAs. The mobile phase ratio and flow rate were identified as critical method parameters (CMPs) and were systematically optimized using face-centered cubic design, evaluating for CAAs, namely peak area, retention time, theoretical plates and peak tailing. Statistical modelization was accomplished followed by response surface analysis for comprehending plausible interaction(s) among CMPs. Search for optimum solution was conducted through numerical and graphical optimization for demarcating the design space. Analytical method validation and subsequent forced degradation studies corroborated the method to be highly efficient for routine analysis of drug and its degradation products. The studies successfully demonstrate the utility of QbD approach for developing the highly sensitive liquid chromatographic method with enhanced method performance.

Effects of olmesartan-based treatment on masked, white-coat, poorly controlled, and well-controlled hypertension: HONEST study.

The authors examined the effects of olmesartan-based treatment on clinic systolic blood pressure (CSBP) and morning home systolic blood pressure (HSBP) in 21,340 patients with masked hypertension (MH), white-coat hypertension (WCH), poorly controlled hypertension (PCH), and well-controlled hypertension (CH) using data from the Home Blood Pressure Measurement With Olmesartan Naive Patients to Establish Standard Target Blood Pressure (HONEST) study. MH, WCH, PCH, and CH were defined using CSBP 140 mm Hg and MHSBP 135 mm Hg as cutoff values at baseline. At 16 weeks, the MH, WCH, PCH, and CH groups had changes in CSBP by -1.0, -15.2, -23.1, and 1.8 mm Hg, and changes in morning HSBP by -12.5, 1.0, -20.3, and 2.0 mm Hg, respectively. In conclusion, in "real-world" clinical practice, olmesartan-based treatment decreased high morning HBP or CBP without excessive decreases in normal morning HBP or CBP according to patients' BP status.

Influence of guidelines on physicians' assessment of blood pressure lowering effects and achievement rate of blood pressure target during transitional period of guidelines.

We studied the agreement rate between achievement of blood pressure (BP) target according to the 2002 Japanese Guidelines for Treatment of Hypertension in the Elderly (EG 2002) and the Japanese Society of Hypertension Guidelines 2004 (JSH 2004) versus a physicians' assessment of BP-lowering efficacy of olmesartan medoxomil in elderly patients. The physicians' assessment more closely agreed with the achievement rate of the BP target according to the EG 2002 than that according to the JSH 2004. This study was started in July 2004, shortly after JSH 2004 was published. Our data suggest that guidelines at the time strongly influence the physicians' assessment and their treatment strategy for individual patients in daily clinical practice.

Possible beneficial effect of olmesartan medoxomil on left atrial function in patients with hypertension : noninvasive assessment by acoustic quantification.

BACKGROUND AND OBJECTIVE: Hypertension alters the diastolic properties of the left ventricle and results in deterioration in the structure and function of the left atrium. We aimed to evaluate whether olmesartan medoxomil has an effect on left atrial function in hypertensive patients. METHODS: Fifty hypertensive patients and 20 controls were included in the study. Hypertensive patients were treated with olmesartan medoxomil for 8 weeks. Before and after treatment, study participants were examined by acoustic quantification and tissue Doppler imaging. Left atrial reservoir function was assessed by end-diastolic volume (EDV), end-systolic volume (ESV), reservoir volume (RV) and peak filling rate (PFR). Left atrial booster pump function was assessed by atrial emptying volume (AEV), atrial emptying fraction (AEF) and peak atrial emptying rate (PAER). Left atrial conduit function was assessed by rapid emptying volume (REV), rapid emptying fraction (REF), REV/AEV ratio, and the ratio of peak rapid emptying rate and PAER (PRER/PAER). RESULTS: Atrial RV and PFR were significantly increased in hypertensive subjects (48.30 +/- 19.28 mL vs 34.35 +/- 14.26 mL, p < 0.001; 267.26 +/- 126.52 mL/s vs 206.81 +/- 107.17 mL/s, p < 0.05) compared with controls, while the REV/AEV ratio was decreased in hypertensive patients compared with controls (2.86 +/- 0.85 vs 3.69 +/- 2.13, p < 0.001). After therapy with olmesartan medoxomil, atrial RV (48.30 +/- 19.28 mL vs 40.50 +/- 17.59 mL) and PFR decreased (267.26 +/- 126.52 mL/s vs 220.40 +/- 108.56 mL/s, p < 0.05) and the REV/AEV ratio increased (2.86 +/- 0.85 vs 3.14 +/- 0.43, p < 0.05) in hypertensive patients. CONCLUSION: Our novel findings indicate that left atrial function is impaired in hypertensive patients, and that olmesartan medoxomil can improve left atrial function in this context. Our study also showed that acoustic quantification is useful for non-invasive evaluation of the benefits of treatment on left atrial function.

Olmesartan medoxomil: current status of its use in monotherapy.

Olmesartan medoxomil is an angiotensin II receptor antagonist. In pooled analyses of seven randomized, double-blind trials, 8 weeks' treatment with olmesartan medoxomil was significantly more effective than placebo in terms of the response rate, proportion of patients achieving target blood pressure (BP) and mean change from baseline in diastolic (DBP) and systolic blood pressure (SBP). Olmesartan medoxomil had a fast onset of action, with significant between-group differences evident from 2 weeks onwards. The drug was well tolerated with a similar adverse event profile to placebo. In patients with type 2 diabetes, olmesartan medoxomil reduced renal vascular resistance, increased renal perfusion, and reduced oxidative stress. In several large, randomized, double-blind trials, olmesartan medoxomil 20 mg has been shown to be significantly more effective, in terms of primary endpoints, than recommended doses of losartan, valsartan, irbesartan, or candesartan cilexetil, and to provide better 24 h BP protection. Olmesartan medoxomil was at least as effective as amlodipine, felodipine and atenolol, and significantly more effective than captopril. The efficacy of olmesartan medoxomil in reducing cardiovascular risk beyond BP reduction is currently being investigated in trials involving patients at high risk due to atherosclerosis or type 2 diabetes.

Olmesartan medoxomil: the seventh angiotensin receptor antagonist.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and adverse effects of olmesartan medoxomil, an angiotensin II receptor antagonist for the treatment of hypertension. DATA SOURCES: Information was obtained from MEDLINE searches (1996-April 2002) of English-language medical literature. Search terms included CS-866, olmesartan, olmesartan medoxomil, RNH-6270 (active metabolite of olmesartan), Benicar, angiotensin receptors, and antihypertensive agents. In addition, references from relevant articles were reviewed for additional citations. The authors independently reviewed literature identified in the searches. Studies evaluating olmesartan (i.e., abstracts, clinical trials, data on file with manufacturer) were considered for inclusion. STUDY SELECTION: All articles identified from data sources with pertinent information regarding olmesartan medoxomil were evaluated, and all information deemed relevant was included in this review. DATA SYNTHESIS: Olmesartan medoxomil is a competitively priced addition to the class of angiotensin II receptor antagonists. Monotherapy with olmesartan medoxomil in once-daily doses of 20-40 mg has produced significant reductions in systolic and diastolic blood pressure in hypertensive patients. Adverse effects have been minimal with olmesartan medoxomil, with dizziness being the only adverse effect occurring more often than with placebo in clinical trials. Additionally, animal studies indicate that olmesartan medoxomil may prove to be useful treatment for diabetic nephropathy, as well as atherosclerosis. CONCLUSIONS: Olmesartan medoxomil has a favorable safety and efficacy profile, with blood pressure-lowering effects comparable to those of other angiotensin receptor blockers (i.e., losartan, valsartan, irbesartan). At this time, formulary decisions will be driven primarily by economic issues. Theoretical benefits of olmesartan medoxomil in reducing atherogenesis and lowering angiotensin II concentrations better than the alternative agents will be determined only with more extensive research.