Population Pharmacokinetic Analysis of Valsartan in Healthy Chinese Subjects.

The study was conducted to establish a population pharmacokinetic (PPK) model of valsartan in Chinese healthy subjects and investigate potential covariate impacts on the pharmacokinetics (PK) parameters. Data from a bioequivalence study with 78 Chinese healthy subjects were retrospectively analyzed to develop a PPK model of valsartan. Phoenix NLME 8.1 was used to build a PPK model and quantify the effects of covariates, such as demographic data and biochemical, on the PK parameters of valsartan. For the healthy Chinese population, valsartan conformed to the two-compartment model with an absorption lag time. In the final PPK model, food affected the absorption rate constant, while aspartate aminotransferase, alanine aminotransferase, and creatinine affected the clearance of the central compartment. The final PPK model was verified to be reproducible, and it can be used to evaluate the PK parameters. This is the first research describing the PPK profile of valsartan in healthy Chinese subjects, and it is expected to provide relevant PK parameters for further study of valsartan.

Sustainable Stabilizer-Free Nanoparticle Formulations of Valsartan Using Eudragit® RLPO.

The bioavailability of the antihypertensive drug valsartan can be enhanced by various microencapsulation methods. In the present investigation, valsartan-loaded polymeric nanoparticles were manufactured from Eudragit® RLPO using an emulsion-solvent evaporation method. Polyvinyl alcohol (PVA) was found to be a suitable stabilizer for the nanoparticles, resulting in a monodisperse colloid system ranging in size between 148 nm and 162 nm. Additionally, a high encapsulation efficiency (96.4%) was observed. However, due to the quaternary ammonium groups of Eudragit® RLPO, the stabilization of the dispersion could be achieved in the absence of PVA as well. The nanoparticles were reduced in size (by 22%) and exhibited similar encapsulation efficiencies (96.4%). This more cost-effective and sustainable production method reduces the use of excipients and their expected emission into the environment. The drug release from valsartan-loaded nanoparticles was evaluated in a two-stage biorelevant dissolution set-up, leading to the rapid dissolution of valsartan in a simulated intestinal medium. In silico simulations using a model validated previously indicate a potential dose reduction of 60-70% compared to existing drug products. This further reduces the expected emission of the ecotoxic compound into the environment.

Potential Implications of Expanded US Food and Drug Administration Labeling for Sacubitril/Valsartan in the US.

Importance: The US Food and Drug Administration (FDA) expanded labeling for sacubitril/valsartan for use in individuals with chronic heart failure (HF) with left ventricular ejection fraction (LVEF) lower than normal. The population-level implications of implementation of sacubitril/valsartan at higher LVEF ranges is unknown. While the Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction (PARAGON-HF) trial did not meet its primary end point, the trial may provide useful information in projecting expected clinical events among treated individuals. Objective: To quantify newly eligible treatment candidates for sacubitril/valsartan under the expanded FDA labeling and to apply treatment effects and the number needed to treat (NNT) to prevent 1 worsening HF event derived from subgroups of the PARAGON-HF trial who fall under the revised FDA label. Design, Setting, and Participants: Newly eligible treatment candidates were estimated by mapping the LVEF distribution from 559 520 adult patients hospitalized between 2014 and 2019 in the Get With The Guidelines-Heart Failure registry to adults self-identifying with HF in the National Health and Nutrition Examination Survey (2015 to 2018). The NNT with 3 years of treatment for 3 end points of interest (total HF hospitalizations, total HF hospitalizations and cardiovascular death, and total HF hospitalizations and urgent HF visits and cardiovascular death) were estimated from the PARAGON-HF trial. Data were analyzed from February to June 2021. Main Outcomes and Measures: Number of worsening HF events prevented or postponed if eligible patients were treated with sacubitril/valsartan for 3 years. Results: Of an estimated 4 682 098 adults, the mean (SE) age was 66.3 (0.8) years, 1 995 037 (42.6%) were women, and 748 045 (16.0%) were Black. The potential number of adults projected to be newly eligible varied by the definition of FDA labeling of lower than normal LVEF from 643 161 (95% CI, 534 433-751 888; LVEF of 41% to 50%) to 1 838 756 (95% CI, 1 527 911-2 149 601; LVEF of 41% to 60%). In the PARAGON-HF trial, the NNT to prevent a worsening HF event (range, 7 to 12 patients) was consistent irrespective of specific LVEF range selected. Comprehensive implementation of sacubitril/valsartan among newly eligible patients was empirically estimated to prevent up to 69 268 (95% CI, 57 558-80 978) worsening HF events (LVEF of 41% to 50%) to 182 592 (95% CI, 151 725-213 460) worsening HF events (LVEF of 41% to 60%). Conclusions and Relevance: The expanded FDA labeling is positioned to substantially increase the potential HF population eligible for sacubitril/valsartan by up to 1.8 million individuals and has the potential to prevent or postpone as many as 180 000 worsening HF events, depending on the definition of normal LVEF.

Nanostructured Valsartan Microparticles with Enhanced Bioavailability Produced by High-Throughput Electrohydrodynamic Room-Temperature Atomization.

The high-throughput drying and encapsulation technique called electrospraying assisted by pressurized gas (EAPG) was used for the first time to produce nanostructured valsartan within microparticles of excipients. Valsartan, a poorly absorbed and lipid-soluble drug, was selected since it is considered a good model for BCS class II drugs. Two different polymeric matrices were selected as excipients, i.e., hydroxypropyl methylcellulose (HPMC) and lactose monohydrate, while Span 20 was used as a surfactant. The produced 80% valsartan loading formulations were characterized in terms of morphology, crystallinity, in vitro release, in vitro Caco-2 cells' permeability, and in vivo pharmacokinetic study. Spherical microparticles of ca. 4 µm were obtained within which valsartan nanoparticles were seen to range from 150 to 650 nm. Wide-angle X-ray scattering and differential scanning calorimetry confirmed that valsartan had a lower and/or more ill-defined crystallinity than the commercial source, and photon correlation spectroscopy and transmission electron microscopy proved that it was dispersed and distributed in the form of nanoparticles of controlled size. In vitro dissolution tests showed that the HPMC formulation with the lowest API particle size, i.e., 150 nm, dissolved 2.5-fold faster than the commercial valsartan in the first 10 min. This formulation also showed a 4-fold faster in vitro permeability than the commercial valsartan and a 3-fold higher systemic exposure than the commercial sample. The results proved the potential of the EAPG processing technique for the production of safe-to-handle microparticles containing high quantities of a highly dispersed and distributed nanonized BCS class II model drug with enhanced bioavailability.

Evaluation of Drug Dissolution Rate in Co-amorphous and Co-crystal Binary Drug Delivery Systems by Thermodynamic and Kinetic Methods.

In order to better explain and predict the dissolution characteristics of binary drug delivery systems (BDDSs), the dissolution behaviors of co-crystal (CC) and co-amorphous (CA) systems of sacubitril (SCB) and valsartan (VST) were evaluated in vitro and in vivo by thermodynamic and kinetic methods. The CCs of SCB and VST were prepared into a CA state through rotary evaporation. Solid-state properties were systematically evaluated. Herein, based on the results from previous studies of single-phase systems, we used thermodynamic methods to evaluate the increase in drug dissolution rate after BDDSs change from the crystalline to the amorphous state. After comparing the predicted and measured dissolution rate enhancement of the CC and CA systems, this paper attempts to explain the dissolution rate characteristics of the BDDSs. We then evaluated the bioavailability of two BDDSs in beagle dogs to confirm that there was no discrepancy in vivo with the results obtained in vitro. The results exhibited that there is strong intermolecular interaction between SCB and VST and good physical stability for the CA system. Compared with the CC, the bioavailability of SCB and VST in the CA system increased by 313.9% and 130.5%, respectively. The predicted dissolution rate ratio between CC and CA systems and their actual intrinsic dissolution rates differed by only a factor of 2.5, demonstrating the good correlation between the predicted and measured values. In the future, this method could be expanded to a variety of new samples and exciting drug prospects.

Drug-Drug Interaction Surveillance Study: Comparing Self-Controlled Designs in Five Empirical Examples in Real-World Data.

Self-controlled designs, specifically the case-crossover (CCO) and the self-controlled case series (SCCS), are increasingly utilized to generate real-world evidence (RWE) on drug-drug interactions (DDIs). Although these designs share the advantages and limitations of within-individual comparison, they also have design-specific assumptions. It is not known to what extent the differences in assumptions lead to different results in RWE DDI analyses. Using a nationwide US commercial healthcare insurance database (2006-2016), we compared the CCO and SCCS designs, as they are implemented in DDI studies, within five DDI-outcome examples: (1) simvastatin + clarithromycin and muscle-related toxicity; (2) atorvastatin + valsartan, and muscle-related toxicity; and (3-5) dabigatran + P-glycoprotein inhibitor (clarithromycin, amiodarone, and verapamil) and bleeding. Analyses were conducted within person-time exposed to the object drug (statins and dabigatran) and adjusted for bias associated with the inhibiting drugs via control groups of individuals unexposed to the object drug. The designs yielded similar estimates in most examples, with SCCS displaying better statistical efficiency. With both designs, results varied across sensitivity analyses, particularly in CCO analyses with small number of exposed individuals. Analyses in controls revealed substantial bias that may be differential across DDI-exposed and control individuals. Thus, both designs showed no association between amiodarone or verapamil and bleeding in dabigatran-exposed but revealed strong positive associations in controls. Overall, bias adjustment via a control group had a larger impact on results than the choice of a design, highlighting the importance and challenges of appropriate control group selection for adequate bias control in self-controlled analyses of DDIs.

Pharmacokinetic interaction study between ligustrazine and valsartan in rats and its potential mechanism.

CONTEXT: Ligustrazine and valsartan are commonly used drugs in the treatment of cardiac and cardiovascular disease. OBJECTIVE: The interaction between ligustrazine and valsartan was studied to investigate the effect of ligustrazine on the pharmacokinetics of valsartan. MATERIALS AND METHODS: The pharmacokinetics of valsartan (10 mg/kg) was investigated in Sprague-Dawley rats divided into three groups (with the pretreatment of 4 or 10 mg/kg/day ligustrazine for 10 days and without the pretreatment of ligustrazine as control) of six rats each. The in vitro experiments in rat liver microsomes were performed to explore the effect of ligustrazine on the metabolic stability of valsartan. RESULTS: Ligustrazine changed the pharmacokinetic profile of valsartan. In the presence of 4 mg/kg ligustrazine, the AUC(0- t ) (385.37 ± 93.05 versus 851.64 ± 104.26 µg/L*h), t1/2 (5.46 ± 0.93 versus 6.34 ± 1.25 h), and C max (62.64 ± 9.09 versus 83.87 ± 6.15 µg/L) of valsartan was significantly decreased, and the clearance rate was increased from 10.92 ± 1.521 to 25.76 ± 6.24 L/h/kg and similar changes were observed in the group with 10 mg/kg ligustrazine (p < 0.05). The metabolic stability of valsartan was also decreased by ligustrazine as the half-life of valsartan in rat liver microsomes decreased from 37.12 ± 4.06 to 33.48 ± 3.56 min and the intrinsic clearance rate increased from 37.34 ± 3.84 to 41.40 ± 4.32 µL/min/mg protein (p < 0.05). DISCUSSION AND CONCLUSIONS: Ligustrazine promoted the metabolism of valsartan via activating CYP3A4. The co-administration of ligustrazine and valsartan should be taken into account.

Pharmacokinetics and Bioequivalence of Two Formulations of Valsartan 80 mg Capsules: A Randomized, Single Dose, 4-Period Crossover Study in Healthy Chinese Volunteers Under Fasting and Fed Conditions.

PURPOSE: To compare the bioequivalence of two formulations of valsartan (80 mg capsules) under fasting and fed conditions in healthy Chinese volunteers using a full-replicate study design. METHODS: A total of 78 Subjects were randomly assigned to fasting cohort (n = 48) or fed cohort (n = 30). Each cohort includes 4 single-dose observation periods and 3-day washout periods. Blood samples were collected at designed time point. Plasma concentration of valsartan was analyzed by a validated LC-MS/MS method. Noncompartmental analysis method was employed to determine the pharmacokinetic parameters. Based on the within-subject standard deviation (SWR) of the reference formulation, either reference-scaled average bioequivalence (RSABE) or average bioequivalence (ABE) method was used to evaluate the bioequivalence of the two formulations. RESULTS: Under fasting conditions, the RSABE method was used to evaluate the bioequivalence of Cmax (SWR>0.294), while ABE method was used to evaluate the bioequivalence of AUC0-t and AUC0-∞. The geometric mean ratio (GMR) of the test/reference for Cmax was 99.52%, and the 95% upper confidence bound was <0. For AUC0-t and AUC0-∞ comparisons, GMRs were 102.07% and 101.92%, and the 90% CIs of the test/reference were 96.28%-108.21%, 96.28%-107.88%, respectively. Under fed conditions, the SWR value of Cmax, AUC0-t and AUC0-∞ all exceeded the cutoff value of 0.294 and therefore, the RSABE method was used. The GMRs for Cmax, AUC0-t and AUC0-∞ were 98.78%, 103.33% and 103.08%, respectively, while the 95% upper confidence bound values were all <0. These results all met the bioequivalence criteria for highly variable drugs. All adverse events were mild and transient. CONCLUSION: In this study, the generic formulation of valsartan 80 mg capsule was considered to be bioequivalent to the reference product under both fasting and fed conditions, and satisfied the requirements for marketing in China. NMPA REGISTRATION NO: CTR20181422.

Blood Pressure-Lowering Profiles and Clinical Effects of Angiotensin Receptor Blockers Versus Calcium Channel Blockers.

Blood pressure-lowering drugs have different blood pressure-lowering profiles. We studied if differences in blood pressure mean and variability can explain the differences in risks of cardiovascular events and death among 15 245 high-risk hypertensive patients randomized to valsartan or amlodipine and followed for 4.2 years in the VALUE trial (Valsartan Antihypertensive Long-Term Use Evaluation). We selected patients with ≥3 visits and performed Cox regression analyses, defining mean blood pressure as a time-dependent covariate and visit-to-visit and within-visit blood pressure variability as the SD. Of 14 996 eligible patients, participants in the valsartan group had higher systolic mean blood pressure by 2.2 mm Hg, higher visit-to-visit systolic variability by 1.4 mm Hg, and higher within-visit systolic variability by 0.2 mm Hg (P values <0.0001). The higher risks of myocardial infarction and stroke in the valsartan group was attenuated after adjustment for mean and variability of systolic blood pressure, from HR 1.19 (95% CI, 1.02-1.39) to 1.11 (0.96-1.30) and from HR 1.13 (0.96-1.33) to 1.00 (0.85-1.18), respectively. The lower risk of congestive heart failure in the valsartan group was accentuated after adjustment, from HR 0.86 (0.74-1.00) to 0.76 (0.65-0.89). A smaller effect was seen on risk of death, from 1.01 (0.92-1.12) to 0.94 (0.85-1.04). In conclusion, the higher risks of myocardial infarction and stroke in patients randomized to valsartan versus amlodipine were related to the drugs' different blood pressure modulating profiles. The risk of congestive heart failure with valsartan was lower, independent of the less favorable blood pressure modulating profile.

Intestinal Permeability and Oral Absorption of Selected Drugs Are Reduced in a Mouse Model of Familial Alzheimer's Disease.

Compared with the significant number of studies reporting altered abundance and function of drug transporters at the blood-brain barrier (BBB) in Alzheimer's disease (AD), the impact of AD on the abundance of intestinal drug transporters and the subsequent effects on oral drug absorption have received little attention. We have reported the altered abundance of some small intestinal drug transporters in a familial mouse model of AD; however, whether this leads to altered oral drug absorption is unknown. The current study examined plasma concentrations of caffeine and diazepam (markers for transcellular passive transport), digoxin (P-glycoprotein substrate), and valsartan (multidrug resistance-associated protein 2 substrate) following oral administration to 8-10 month old female wild-type (WT) and APPswe/PSEN1dE9 (APP/PS1) transgenic mice, a commonly used mouse model of familial AD. The plasma exposure of valsartan and digoxin was significantly (p < 0.05) lower in APP/PS1 animals compared with WT mice, whereas the plasma concentrations of the passive transcellular markers caffeine and diazepam did not significantly differ between the two genotypes. To assess whether the reduced oral absorption of valsartan and digoxin was due to decreased intestinal transport, the ex vivo transport of the previously mentioned drugs and mannitol (a marker of paracellular transport) across the jejunum of WT and APP/PS1 mice was assessed over 120 min. In line with the in vivo absorption studies, the permeability of caffeine and diazepam did not significantly differ between WT and APP/PS1 mice. The permeability of 3H-digoxin through the APP/PS1 mouse jejunum was lower than that measured through the WT jejunum; the average amount (relative to dose applied) permeating the tissue over 120 min was 0.22 ± 0.11% (mean ± SD) for the APP/PS1 jejunum and 0.85 ± 0.3% for the WT jejunum. A 1.9-fold reduction in the average amount of valsartan permeating the jejunum of APP/PS1 mice relative to that of WT mice was also detected. Although no apparent morphological alterations were observed in the jejunal tissue of APP/PS1 mice, the permeability of 14C-mannitol across the jejunum from APP/PS1 mice was lower than that across the WT jejunum (Papp= 10.7 ± 3.7 × 10-6 and 6.0 ± 3.4 × 10-6 cm/s, respectively), suggesting tightened paracellular junctions in APP/PS1 mice. These studies are the first to demonstrate, in APP/PS1 mice, reduced intestinal permeability and the absorption of drugs commonly prescribed to people with AD for their comorbidities. If these findings translate to people with AD, then modified dosing regimens may be necessary for selected drugs to ensure that their plasma concentrations remain in the effective range.

Herb-Drug Interaction of Red Ginseng Extract and Ginsenoside Rc with Valsartan in Rats.

The purpose of this study was to investigate the herb-drug interactions involving red ginseng extract (RGE) or ginsenoside Rc with valsartan, a substrate for organic anion transporting polypeptide (OATP/Oatp) transporters. In HEK293 cells overexpressing drug transporters, the protopanaxadiol (PPD)-type ginsenosides- Rb1, Rb2, Rc, Rd, Rg3, compound K, and Rh2-inhibited human OATP1B1 and OATP1B3 transporters (IC50 values of 7.99-68.2 µM for OATP1B1; 1.36-30.8 µM for OATP1B3), suggesting the herb-drug interaction of PPD-type ginsenosides involving OATPs. Protopanaxatriol (PPT)-type ginsenosides-Re, Rg1, and Rh1-did not inhibit OATP1B1 and OATP1B3 and all ginsenosides tested didn't inhibit OCT and OAT transporters. However, in rats, neither RGE nor Rc, a potent OATP inhibitor among PPD-type ginsenoside, changed in vivo pharmacokinetics of valsartan following repeated oral administration of RGE (1.5 g/kg/day for 7 days) or repeated intravenous injection of Rc (3 mg/kg for 5 days). The lack of in vivo herb-drug interaction between orally administered RGE and valsartan could be attributed to the low plasma concentration of PPD-type ginsenosides (5.3-48.4 nM). Even high plasma concentration of Rc did not effectively alter the pharmacokinetics of valsartan because of high protein binding and the limited liver distribution of Rc. The results, in conclusion, would provide useful information for herb-drug interaction between RGE or PPD-type ginsenosides and Oatp substrate drugs.

Preparation and appraisal of self-assembled valsartan-loaded amalgamated Pluronic F127/Tween 80 polymeric micelles: Boosted cardioprotection via regulation of Mhrt/Nrf2 and Trx1 pathways in cisplatin-induced cardiotoxicity.

This study aimed to develop valsartan (VAL)-loaded mixed micelles and investigate their cardioprotective potential and molecular mechanisms through Mhrt/Nrf2 and Trx1 pathways. VAL-loaded mixed micelles have not been elaborated and their impact on Mhrt/Nrf2 and Trx1 pathways has not been yet inspected. VAL-loaded mixed micelles were prepared, incorporating Pluronic F127 and Tween 80, adopting thin-film hydration method. The micelles were evaluated for drug entrapment efficiency, loading characteristics, particle size, morphology, in vitro drug release and micelles storage stability. The pharmacokinetic studies were explored in rats. Also, VAL suspension and mixed micelles were tested in cisplatin-induced cardiotoxicity in rats either pre to or simultaneously with cisplatin. RNA expression of lnc Mhrt and protein expression of Nrf2, Trx1, Ask1, AMPK and caspase 3, oxidative stress and cardiac injury markers besides tailed DNA% by comet assay were assessed. Pharmacokinetic studies evoked a 3.75-fold increase in oral bioavailability as compared with VAL suspension. Overall, treatment with VAL-loaded mixed micelles was superior to VAL suspension in decreasing oxidative stress and cardiac injury markers and restoring the abnormalities occurred in Mhrt/Nrf2 and Trx1 pathways. Thus, mixed micelles would be promising nanocarrier for the engineering of VAL with reinforced pharmacokinetics and cardioprotection characteristics.

Pharmacokinetic and Safety Profiles of a Fixed-Dose Combination of Amlodipine, Valsartan, and Atorvastatin: A 3-Period Replicate Crossover Study.

The objective of study was to compare the pharmacokinetic and safety profiles of a fixed-dose combination (FDC) formulation of 5/160/20 mg amlodipine/valsartan/atorvastatin with those of separate formulations of a 5/160-mg amlodipine/valsartan tablet and a 20-mg atorvastatin tablet. This was a randomized, open-label, single-dose, 3-sequence, 3-period replicate crossover study with 42 subjects. Serial blood samples for pharmacokinetic assessment were collected up to 72 hours postdose. For establishing bioequivalence (BE) for amlodipine, valsartan, and atorvastatin, a reference-scaled average BE approach was used if applicable, as well as the conventional limit of 0.80-1.25. The 90% confidence intervals (CIs) for the geometric mean ratios (GMRs) for the maximum plasma concentration (Cmax ) and the area under the curve to the last measurable concentration (AUCt ) between the FDC and separate formulations were within the 0.80-1.25 limit for all analytes but atorvastatin. The estimated within-subject standard deviation of the log-transformed values of the separate formulations, the reference intervention, was 0.3804 for the Cmax of atorvastatin, being set at 0.7489-1.3352 for the BE acceptance limit. For both the Cmax and AUCt for atorvastatin, the GMRs lay within 0.80-1.25, and the 90%CIs for the GMRs were within the BE acceptance limit. This 3-period replicate crossover study demonstrated the BE of the FDC formulation of amlodipine, valsartan, and atorvastatin and the separate formulations of an amlodipine/valsartan tablet and an atorvastatin tablet. A similar incidence of treatment-emergent adverse events (TEAEs) was observed in both interventions, and headache was the most common TEAE.

The Evaluation of Valsartan Biopharmaceutics Properties.

BACKGROUND: Solubility, intestinal permeability and dissolution are the main factors that govern the rate and extent of drugs absorption and are directly related to bioavailability. Biopharmaceutics Classification System (BCS) is an important tool which uses in vitro results for comparison with bioavailability in vivo (biowaiver). Valsartan is widely used in the treatment of hypertension and shows different BCS classification in the literature (BCS class II or III). OBJECTIVE: This work proposes the study of valsartan biopharmaceutics properties and its BCS classification. METHODS: High Performance Liquid Chromatography (HPLC) method was developed and validated to quantify the drug in buffers pH 1.2, 4.5 and 6.8 respectively. Valsartan solubility was determined in these three different media using shake flask method and intrinsic dissolution rate. Evaluation of dissolution profile from coated tablets was conducted. RESULTS: The low solubility (pH 1.2 and 4.5) and high solubility (pH 6.8) were observed for both solubility methods. Permeability data reported from the literature showed that valsartan is a low permeability drug. Valsartan presented the rapid release profile only in pH 6.8. CONCLUSION: We defined that valsartan is a class IV drug, in disagreement with what has been published so far. It is important to emphasize that the conditions considered here are indicated to define the biopharmaceutics classification by regulatory agencies.

Co amorphous valsartan nifedipine system: Preparation, characterization, in vitro and in vivo evaluation.

Co amorphous systems are supersaturated drug delivery systems which offer a basic platform for delivery of multicomponent adducts (combination of more than one active pharmaceutical ingredient (API)) and/or as a fixed dose combination therapy, in addition to their potential to improve the apparent solubility, dissolution rate and ultimately bioavailability of poorly water soluble APIs. In the present work, a new drug-drug co amorphous system namely valsartan-nifedipine was prepared by quench cooling technique. Prepared co amorphous system was characterized for its solid state behavior with the help of Fourier Transform Infrared spectroscopy (FTIR), Differential Scanning Calorimetry (DSC) and Powder X Ray Diffractometry (PXRD). The optimized co amorphous system was stable for 1 month when exposed to accelerated stability condition (40 ±â€¯2 °C and 75 ±â€¯5% RH). The improved stability of amorphous nifedipine in co amorphous system was attributed to improved miscibility and intra and intermolecular non-covalent interactions mainly due to presence of hydrogen bonding between valsartan and nifedipine which was studied by FTIR analysis. Co amorphous systems were evaluated by mainly in vitro dissolution and in vivo benefit. In vitro dissolution study showed nearly 5.66 folds and 1.61 folds improvement which was translated to 3.63 and 2.19 times enhancement in vivo Cmax for nifedipine and valsartan respectively.

MOF Capacitates Cyclodextrin to Mega-Load Mode for High-Efficient Delivery of Valsartan.

PURPOSE: To investigate the mechanism of enhancing solubility and bioavailability of water-insoluble drug, valsartan (VAL), with being mega-loaded by cyclodextrin metal organic framework (CD-MOF). METHODS: VAL was successfully mega-loaded into CD-MOF by magnetic agitation of VAL in ethanolic solution. Characterizations including powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), synchrotron radiation-based Fourier transform-infrared spectroscopy (SR-FTIR) 13C solid-state nuclear magnetic resonance spectroscopy ( 13C SS-NMR), nitrogen gas adsorption, and small-angle X-ray scattering (SAXS) were carried out to confirm the mechanism and incorporation behavior of VAL in CD-MOF. Ball milling process combined with molecular modeling was also used to confirm the mechanism. Improvement of bioavailability in vivo was confirmed by pharmacokinetic experiment in beagles. RESULTS: As a carrier with payload 150% higher than conventional CD complexation, CD-MOF included molecules of VAL as complexations in the chambers of (γ-CD)2, and nanoclusters in the confined spherical cages of (γ-CD)6 confirmed by SAXS and 13C SS-NMR. Ball milling combined with molecular modeling inferred that the reduced release rate of the milled CD-MOF with ultrahigh drug payload was mainly due to the partial aggregation of the VAL nanoclusters. The molecules of VAL as nanoclusters in the cages of (γ-CD)6 are critical in dramatically improving the apparent solubility (39.5-fold) and oral bioavailability (1.9-fold) of VAL in contrast to γ-CD inclusion. CONCLUSIONS: The new understanding of drug nanoclusters in CD-MOF will help to design more efficient drug delivery systems using CD-MOF carrier with nanocavities.

Pharmacokinetic Drug Interactions Between Amlodipine, Valsartan, and Rosuvastatin in Healthy Volunteers.

INTRODUCTION: Amlodipine, valsartan, and rosuvastatin are among the medications widely coadministered for the treatment of hyperlipidemia accompanied by hypertension. The aim of this study was to investigate the possible pharmacokinetic drug-drug interactions between amlodipine, valsartan, and rosuvastatin in healthy Korean male volunteers. METHODS: In this phase 1, open-label, multiple-dose, two-part, two-period, fixed-sequence study, the enrolled subjects were randomized into two parts (A and B). In part A (n = 32), each subject received one fixed-dose combination (FDC) tablet of amlodipine/valsartan 10 mg/160 mg alone for 10 consecutive days in period I, and the same FDC for 10 days with concomitant 7-day administration of 20 mg rosuvastatin in period II. In part B (n = 25), each subject received rosuvastatin alone for 7 days in period I, and the FDC for 10 days with concomitant 7-day administration of rosuvastatin in period II. In both parts, there was a 12-day washout between periods. Serial blood samples were collected for up to 72 h for amlodipine and rosuvastatin, and for up to 48 h for valsartan after the last dose of each period. The plasma concentrations of amlodipine, valsartan, and rosuvastatin were determined by using liquid chromatography-tandem mass spectrometry. RESULTS: Fifty-seven subjects were enrolled; 30 and 25 subjects completed part A and part B, respectively. The geometric mean ratios and 90% confidence intervals for the maximum plasma concentration at steady state (Cmax,ss) and the area under the plasma concentration-time curve over the dosing interval at steady state (AUCτ,ss) were 0.9389 (0.9029-0.9763) and 0.9316 (0.8970-0.9675) for amlodipine, 0.7698 (0.6503-0.9114) and 0.7888 (0.6943-0.8962) for valsartan, and 0.9737 (0.8312-1.1407) and 0.9596 (0.8826-1.0433) for rosuvastatin, respectively. Of the 57 subjects enrolled in this study, 10 subjects experienced 13 adverse events (AEs); no severe or serious AEs were reported. CONCLUSION: When amlodipine, valsartan, and rosuvastatin were coadministered to healthy volunteers, the pharmacokinetic exposure to valsartan was decreased, but no change in exposure to amlodipine and rosuvastatin occurred. All treatments were well tolerated. CLINICAL TRIAL REGISTRATION: https://cris.nih.go.kr CRIS KCT0001660. FUNDING: KyungDong Pharmaceutical Corp. Ltd., Seoul, Republic of Korea.

Efecto inicial del sacubitrilo-valsartán sobre la capacidad funcional en pacientes con insuficiencia cardiaca con fracción de eyección reducida: estudio piloto / Early sacubitril/valsartan-driven benefit on exercise capacity in heart failure with reduced ejection fraction: a pilot study

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Combinação dose fixa de hidroclorotiazida (12, 5 mg) e valsartana (160 mg): Desenvolvimento de metodologia de dissolução in vitro e in silico para avaliar os perfis de dissolução dos produtos comercializados no Brasil e Peru / Fixed dose combination of hydrochlorothiazide (12. 5 mg) and valsartan (160 mg): Development of in vitro and in silico dissolution methodology to evaluate the dissolution profiles of products marketed in Brazil and Peru

Hidroclorothiazida (HTZ) e valsartana (VAL) são fármacos pouco solúveis em meio aquoso e pertencem às classes IV e II do Sistema de Classificação Biofarmacêutica (SCB), respectivamente. O objetivo deste trabalho foi desenvolver um método para avaliar o perfil de dissolução de formas farmacêuticas sólidas de dose fixa combinada contendo HTZ (12,5 mg) e VAL (160 mg) usando ferramentas in silico para avaliar os perfis de dissolução de produtos comercializados no Brasil e Peru. O presente trabalho foi dividido em 4 capítulos. No Capítulo I, foi determinada a solubilidade da HTZ e VAL pelo método shake-flask e potenciométrico, no qual foi possível demonstrar que existe correlação entre ambos os métodos e que HTZ e VAL são solúveis em tampão fosfato pH 6,8. No Capítulo II, um método cromatográfico em HPLC foi desenvolvido com base em Quality by Design (QbD), com auxílio do software Fusion®, no qual foi estabelecido uma zona de confiança dos parâmetros, que garantiu a robustez do método. O Capítulo III descreve o desenvolvimento de um método de dissolução utilizando ferramenta in silico (DDDplus®) na qual foi definido um delineamento experimental do tipo fatorial completo 33 usando como fatores a formulação, utilização de âncora e velocidade de agitação. Para os ensaios de dissolução in vitro, foi proposto um outro delineamento fatorial 3(3-1) com o intuito de obter as constantes de calibração das simulações in silico. Através de uma análise estatística das eficiências de dissolução obtidas nas simulações, foram avaliados os efeitos e as interações entre os fatores. Assim, as condições finais do método de dissolução estabelecidas foram: 900 mL de tampão fosfato pH 6,8 como meio de dissolução, 75 rpm de velocidade de agitação, e utilização de âncora para evitar a flutuação das formulações. O método desenvolvido foi empregado, no contexto do Capítulo IV, para avaliar o perfil de dissolução dos produtos contendo HTZ e VAL comercializados no Brasil e no Peru. Por análise multivariada, a eficiência de dissolução (ED), tempo médio de dissolução (MDT) e as porcentagens de dissolução de 5 até 60 minutos foram utilizadas para agrupar as formulações em grupos distintos. Embora os perfis de dissolução mostrem similaridade entre todas as formulações avaliadas, o produto referência se destacou por apresentar uma maior ED comparado com as outras formulações, devido à maior liberação nos primeiros 5 minutos de ensaio. Concluiu-se que o método proposto, além de garantir a liberação total de HTZ e VAL a partir das formulações, possui adequado poder discriminativo

Hydrochlorothiazide (HTZ) and valsartan (VAL) are poorly soluble drugs in aqueous medium and belong to classes IV and II of the Biopharmaceutical Classification System (BCS), respectively. The objective of this study was to develop a dissolution method to evaluate the dissolution profile of solid pharmaceutical forms of combined dose containing HTZ (12.5 mg) and VAL (160 mg) using in silico tools to evaluate the dissolution profiles of products sold in Brazil and Peru. The present study was divided into four chapters. In Chapter I, the HTZ and VAL solubility were determined by the shake-flask and potentiometric methods, in which it was possible to demonstrate that there is a correlation between both methods and that HTZ and VAL are soluble in pH 6.8 phosphate buffer. In Chapter II, a chromatographic method in HPLC was developed based on Quality by Design (QbD), using the Fusion® software, in which a zone of confidence of the parameters was established, which ensured the robustness of the method. Chapter III presents the development of a dissolution method using in silico (DDDplusTM) as a tool, in which an experimental design of the complete factorial type 33 was defined using as factors: the formulation, use of sinker and agitation speed. For in vitro dissolution assays, another factor design 3(3-1) was proposed to obtain the calibration constants of the in silico simulations. Through a statistical analysis of the dissolution efficiencies obtained in the simulations, the effects and interactions between the factors were evaluated. Thus, the final conditions of the dissolution method established were: 900 mL of pH 6.8 phosphate buffer as a dissolution medium, 75 rpm of stirring speed, and use of sinker to avoid the fluctuation of the formulations. The method developed was used, in the context of Chapter IV, to evaluate the dissolution profile of HTZ and VAL products marketed in Brazil and Peru. By multivariate analysis, the dissolution efficiency (ED), mean dissolution time (MDT) and the dissolution percentages from 5 to 60 minutes were used to group the formulations in different groups. Although the dissolution profiles show a similarity between all the evaluated formulations, the reference product stood out for presenting a higher ED compared to the other formulations, due to the higher release in the first 5 minutes of the test. It was concluded that the proposed method, besides guaranteeing the total release of HTZ and VAL from the formulations, has adequate discriminatory capacity

Identification of beagle food taking patterns and protocol for food effects evaluation on bioavailability.

Food is a known primary role to the exposure of the drugs orally administered. Since each animal may have unique food taking pattern and it is difficult to manipulate the food taking to animals, there lacks rationalized protocol for the food effects in pre-clinic study. The objective of this study was to identify the beagle food taking patterns and demonstrate their effects on bioavailability in valsartan. Herein, four types of food taking patterns of beagle were identified via inter-day and intra-day analysis, and named as Persisting, Pulsing, Postponing, Pushing ("4P Modes"), respectively, which were also validated by principal component analysis (PCA). Interestingly, food intake resulted in a reduced area under the concentration-time curve (AUC0-12h), maximum concentration (Cmax) and absorption rate, whilst the reduction varied in "4P Modes" of food taking. General considerations in the design of experiment for food effect to the bioavailability in beagles have been established as: to recognize the food taking patterns in each animal, to confirm the inter-day stability of the food taking behaviors, to trace the food taking patterns in parallel with plasma sampling. In conclusion, the right animals with proper food taking patterns should be assessed and selected for pre-clinic bioavailability evaluations.