Fixed-dose Combination Research Articles

Spironolactone vs Amiloride for Resistant Hypertension: A Randomized Clinical Trial.

Amiloride has been proposed as an alternative to spironolactone for treating resistant hypertension. However, no randomized clinical trials have compared the efficacy of spironolactone and amiloride in patients with resistant hypertension. To determine whether amiloride is noninferior to spironolactone in reducing home-measured systolic blood pressure (SBP) in patients with resistant hypertension. Prospective, open-label, blinded end-point randomized clinical trial conducted at 14 sites in South Korea. From November 16, 2020, to February 29, 2024, 118 patients with home SBP of 130 mm Hg or greater after a 4-week run-in period with a fixed-dose triple medication combination (angiotensin receptor blocker, calcium channel blocker, and thiazide) were enrolled. Patients were randomized in a 1:1 ratio to receive 12.5 mg/d of spironolactone (n = 60) or 5 mg/d of amiloride (n = 58). If home SBP remained 130 mm Hg or greater and serum potassium was less than 5.0 mmol/L after 4 weeks, dosages were increased to 25 mg/d and 10 mg/d, respectively. The primary end point was the between-group difference in home SBP change at week 12, with a noninferiority margin of -4.4 mm Hg for the lower bound of the confidence interval. Secondary end points included achievement rates of home- and office-measured SBP of less than 130 mm Hg. The median age of the study population was 55 years, with 70% male. There were no differences between groups in demographic characteristics other than use of α-blockers (8.6% in the amiloride group and 0% in the spironolactone group). The mean baseline home SBPs were 141.5 (SD, 7.9) mm Hg and 142.3 (SD, 8.5) mm Hg in the amiloride and spironolactone groups, respectively. At week 12, mean home SBP measurements were changed from baseline by -13.6 (SD, 8.6) mm Hg and -14.7 (SD, 11.0) mm Hg in the amiloride and spironolactone groups, respectively (between-group difference in change, -0.68 mm Hg; 90% CI, -3.50 to 2.14 mm Hg), with amiloride demonstrating noninferiority to spironolactone. Home-measured achievement rates of SBP less than 130 mm Hg in the amiloride and spironolactone groups were 66.1% and 55.2%, respectively, and office-measured achievement rates of SBP less than 130 mm Hg were 57.1% and 60.3%, respectively, with no difference between the 2 groups. One case of hyperkalemia-related discontinuation occurred in the amiloride group, with no cases of gynecomastia in either group. Amiloride was noninferior to spironolactone in lowering home SBP, suggesting that it could be an effective alternative for treatment of resistant hypertension. ClinicalTrials.gov Identifier: NCT04331691.

Correction to: Antihypertensive Medication Regimens Used by US Adults With Hypertension and the Potential for Fixed-Dose Combination Products: The National Health and Nutrition Examination Surveys 2015 to 2020.

Correction to: Antihypertensive Medication Regimens Used by US Adults With Hypertension and the Potential for Fixed-Dose Combination Products: The National Health and Nutrition Examination Surveys 2015 to 2020.

Ginsenoside CK and retinol on UVA-induced photoaging exert the synergistic effect through antioxidant and antiapoptotic mechanisms

Retinol and retinoids can effectively intervene skin aging process, but usually induce skin intolerance. In this study, we aimed to determine the synergistic anti-aging effects of retinol and two retinol derivatives-hydroxypinacolone retinoate (HPR) and retinol palmitate (VAPA) combined with ginsenoside CK in terms of preventing and treating the UVA radiation-induced skin aging. We found that the combination formulation of retinol and ginsenoside CK alleviated the inhibition of photoaging proliferation of HaCaT cells caused by UVA, and reduced the proportion of senescence. Additionally, the combination of retinol, HPR, VAPA with ginsenoside CK significantly down-regulated the expression of P53 and P21, up-regulated P63 in UVA irradiated cells, and had potential anti-apoptotic activity. Ginsenoside CK intervention also inhibited the degradation of collagen and elastin by reducing the expression of matrix metalloproteinases, and significantly alleviated oxidative stress. Further transcriptomic and molecular docking studies suggested that ginsenoside CK may play an anti-photoaging role by binding to the active pocket of AKR1C1 and AKR1C2 proteins. Zebrafish experiment showed that retinol combined with ginsenoside CK had the effect of reducing skin toxicity. In conclusion, our results show that retinol, HPR and VAPA combined with ginsenoside CK have good anti-aging and irritation-reducing effects in vitro and in vivo.

Precision-engineered Carrageenan Gels: Boosting the Efficacy, Selectivity, and Release of Celecoxib for Lung Cancer Therapy.

Lung cancer is one of the most widespread malignancies among all types of cancers. There is uncertainty in its treatment because of the selectivity. The investigation is aimed to enhance therapeutic efficacy through targeted improvements in drug selectivity and reduced toxicity by analyzing well-accepted cyclooxygenase (COX)-2, which is an enzyme target and a known therapeutic target for anti-inflammatory and antitumor agents. The objective of the present research was to identify the most suitable counterpart for celecoxib, which would produce synergistic effects and improve the selectivity index, safety, and efficacy of targeting cancer cells. The HOPE-62 cancer cell line and noncancerous LLC-MK2 cell line were used to analyze the activity of the prepared formulations. The effectiveness was compared by calculating the half-maximal inhibitory concentration (IC50) values of carrageenan, celecoxib, and celecoxib embedded with carrageenan. The release pattern of celecoxib from the carrageenan matrix was also determined by using a trans-diffusion cell; moreover, the binding sites of carrageenan and celecoxib were also evaluated through in silico molecular docking studies. Carrageenan showed promising anticancer activity, with an IC50 value of 17.3±2 μM against the HOPE- 62 cell line. When blended with celecoxib (15.6±2 μM), the combination achieved enhanced efficacy and improved selectivity over celecoxib alone (IC50 of 10.3±1.5 μM). In noncancerous LLC-MK2 cells, the IC50 values were observed to be significantly higher: 1484 ±6 μM in the combined formulation and with IC50 values of 559±3 μM and 878±4 μM, respectively, in celecoxib and carrageenan alone. The carrageenan-embedded celecoxib exhibited a significant increase in the selectivity index from 32 to 144, which suggests enhanced anticancer activity with a favorable safety profile. Initially, sustained release of celecoxib from the blend was at a higher rate, but steadily maintained rates were. The In-silico docking studies also supported the synergistic activity of the combined form through separate interaction patterns without interfering with others. These findings underscore the therapeutic potential of excipient-drug blending strategies to achieve synergistic effects, excellent selectivity, and reduced toxicity in cancer treatments.

Eco-Friendly UV/Vis Spectrophotometric Determination of an Anticonvulsant and Cobalamin-Based Supplement in Bulk and Dosage Forms

Abstract A simple, precise, accurate, and economical UV spectrophotometric method was developed for the simultaneous estimation of lacosamide and cobalamin in bulk and tablet dosage forms. The method was validated as per ICH guidelines for parameters including linearity, accuracy, precision, robustness, and sensitivity. Both drugs followed Beer-Lambert’s law in the concentration range of 0.1–0.9 mg/mL for lacosamide and 0.1–0.9 µg/mL for cobalamin, with a correlation coefficient of 0.991. The method showed good sensitivity, with low limits of detection and quantification. The percentage recovery was found to be 99.13–100.2% for lacosamide and 97.46–101.25% for cobalamin, within acceptable limits. Assay results were 100.01% and 100.22% for lacosamide and cobalamin respectively, indicating accuracy. Precision was confirmed by %RSD values below 2%. Robustness was demonstrated by minor changes in NaOH concentration and detection wavelengths. The method showed no interference from excipients and is suitable for routine quality control. Thus, the developed method is a reliable alternative for the simultaneous analysis of lacosamide and cobalamin in combined pharmaceutical formulations. Keywords: Anticonvulsant, Lacosamide, Cobalamin, UV Spectroscopy, Method Validation

Rationale and Design of an Exploratory, Randomized, Open-Label, Multicenter Clinical Trial to Investigate the Efficacy of Long-Acting β2-Agonist/Long-Acting Muscarinic Antagonist on Heart Failure Complicated by Chronic Obstructive Pulmonary Disease (COPD-HF Trial).

Chronic obstructive pulmonary disease (COPD) is one of the most common comorbidities in patients with chronic heart failure (CHF). A growing number of patients are suffering from both COPD and CHF, and these conditions worsen each other. Inhaled bronchodilator therapy with long-acting muscarinic antagonist (LAMA) and long-acting β2-agonist (LABA) in combination is currently the mainstay of treatment for COPD. However, the effect of LAMA/LABA on HF with COPD remains unknown. The COPD-HF trial is a multicenter, double-arm, open-label, exploratory, investigator-initiated clinical study to investigate the effect of LAMA/LABA on HF in patients suffering from both COPD and CHF. The participants are randomly assigned (1 : 1) to the LAMA/LABA (tiotropium+olodaterol FDC (fixed-dose combination) 5/5 ug) group (once a day, 2 inhalations) or non-pharmacological treatments for COPD as a control group. The planned number of patients to be enrolled in this trial is 54 in total (27 in each group). The participants are followed up for 12 weeks with and without LAMA/LABA. The primary endpoint is the change in plasma B-type natriuretic peptide levels from the baseline to the end of this study (12 weeks). The COPD-HF trial will investigate the efficacy of LAMA/LABA on HF in patients with COPD and CHF.

Inhalation safety and tolerability of a novel fixed-dose combination of glycopyrronium–vilanterol powder in Wistar rats

Fixed-dose combinations (FDCs) offer therapeutic benefits like enhanced efficacy, reduced adverse effects, and better patient compliance, making them cost-effective. They are particularly effective in managing chronic obstructive pulmonary disease (COPD). Combining a long-acting muscarinic antagonist with a long-acting beta-agonist improves lung function, reduces the need for rescue bronchodilators, alleviates respiratory symptoms, and enhances the overall quality of life in COPD patients. This study evaluated the safety and tolerability of a novel FDC containing vilanterol, a selective β2-adrenoreceptor agonist, and glycopyrronium, an antimuscarinic agent, in Wistar rats. Vilanterol promotes bronchodilation, while glycopyrronium reduces bronchoconstriction. Repeated-dose toxicity testing at three dosage levels (6.25 + 12.5 mcg/kg/day, 12.5 + 25 mcg/kg/day, and 25 + 50 mcg/kg/day) through nose-only exposure showed that the FDC was well-tolerated, with no significant clinical signs of toxicity. Key parameters, including body weight, feed consumption, ophthalmic examination, clinical pathology, and bronchoalveolar lavage fluid analysis, showed no adverse effects. Minimal, non-dose-related microscopic lesions and normal alveolar macrophage responses were observed. The no-observed-adverse-effect level, based on actual concentration and duration of exposure, was established at 25 + 50 mcg/kg/day, indicating the FDC’s safety and suitability for further development in COPD management.

Flexipill: A novel 3D printed flexible dose combination with a floating element.

Flexipill: A novel 3D printed flexible dose combination with a floating element.

Fixed-dose combination of obicetrapib and ezetimibe for LDL cholesterol reduction (TANDEM): a phase 3, randomised, double-blind, placebo-controlled trial.

Fixed-dose combination of obicetrapib and ezetimibe for LDL cholesterol reduction (TANDEM): a phase 3, randomised, double-blind, placebo-controlled trial.

Efficacy and Safety of the Fixed-Dose Combination of Atorvastatin/Fenofibrate Versus Atorvastatin on the Lipid Profile of Patients with Type 2 Diabetes and Dyslipidemia.

In dyslipidemia associated with type 2 diabetes (T2DM), elevated triglycerides (TG), increased low-density lipoprotein cholesterol (LDL-C), and decreased high-density lipoprotein cholesterol (HDL-C) levels are commonly found, resulting in a high prevalence of mixed dyslipidemia among patients with T2DM. Therefore, the combination therapy of atorvastatin/fenofibrate may be useful for simplifying pharmacological regimens, enhancing adherence, and requiring fewer doses of each drug to achieve the target, which decreases the number of adverse events. We conducted a randomized multicenter, double-blind clinical trial of patients with T2DM and mixed dyslipidemia to evaluate the magnitude of change in lipid profile with a fixed-dose combination (FDC) therapy group of atorvastatin 20mg/fenofibrate 160mg (G_FDC) versus atorvastatin 20mg monotherapy group (G_M), both oral route, one tablet every 24h. The magnitude of change in the lipid profile at 2 and 4months was compared within each group and between groups using the analysis of variance (ANOVA) test. A p value ≤ 0.05 was considered statistically significant. A total of 76 patients were included (38 per group), with an age of 56.7 ± 10.2years, and 56.6% were women. The values at 4months for G_FDC vs. G_M were as follow: TG mg/dL (-144.3 vs. -64.0, p = 0.004), TG percentage change (%C) (-47.9 vs. -33.1, p = 0.007); LDL-C mg/dL (-50.5 vs. -51.7, p = 0.784), LDL-C %C (-42.5 vs. -45.6, p = 0.899). The percentage of patients who achieved the targets for triglycerides (TG) was 56.7% compared to 43.8% (p = 0.309), while for LDL-C, it was 73.3% compared to 78.1% (p = 0.660). Finally, the predictive cardiovascular risk indices (∆ of change) showed a TG/HDL index of -3.9 ± 4.6 vs. -1.5 ± 2.9 (p = 0.015) and a Tg/glucose index of -0.7 ± 0.5 vs. -0.3 ± 0.4 (p = 0.003). The FDC therapy of atorvastatin 20mg/fenofibrate 160mg achieved a greater percentage reduction in lipid profile than atorvastatin alone. No differences in adverse events were observed between the groups. ClinicalTrials.gov No. NCT04882293, registration date: February 28, 2022.

Greenness, blueness, and whiteness evaluation of a quantitative nuclear magnetic resonance procedure for concurrent assay of aspirin and omeprazole in their single and fixed-dose combined tablets

The Food and Drug Administration recently approved a fixed dose combination of aspirin and omeprazole that has been introduced for the treatment of gastrointestinal disorders, as it reduces the risk of upper gastrointestinal and cardiovascular adverse events in aspirin-treated patients. Therefore, an optimized eco-friendly, simple, fast, and precise quantitative nuclear magnetic resonance spectroscopy technique was presented for the concurrent estimation of that mixture in their single and combined dosage forms. The quantitative nuclear magnetic resonance spectroscopy concurrent estimation of both drugs was achieved using phloroglucinol as the internal standard and dimethyl sulfoxide as a deuterated solvent. An ideal set of acquisition parameters was determined to be 128 scans, 10 s relaxation latency, and 90° pulse angle. The selected quantitative signal of aspirin was the doublet of doublet signal appeared at 7.945 ppm, while that of omeprazole was the singlet signal at 8.18 ppm. The singlet signal at 5.69 ppm was selected for the internal standard. The spectra were subjected to integration, baseline correction, and auto phase correction. The developed quantitative proton nuclear magnetic resonance spectroscopy method was found to be rectilinear over the range of 0.05–4.0 mg mL−1 for both drugs. The detecting and quantifying limits for both drugs were approximately 0.01 and 0.03 mg mL−1, respectively. Neither labelling nor pretreatment steps were needed to assay the studied drugs using our developed quantitative nuclear magnetic resonance spectroscopy method. The proposed nuclear magnetic resonance spectroscopy approach was effectively evaluated in terms of linearity (r = 0.9999), accuracy, and precision (%RSD < 1.08). Furthermore, the suggested technique was investigated to analyze the studied drugs in their single and combined dosages. This work enables clinicians to simultaneously monitor aspirin and omeprazole levels in both single and fixed-dose combination tablets, ensuring precise dosing and effective treatment management. For patients, it supports safer therapy by reducing the risks associated with improper dosing or drug interactions in combination therapies. After evaluating the method's greenness, whiteness and blueness, it was determined that the suggested approach was environmentally friendly. The suggested approach was compared with the previously reported methods from both an analytical and eco-friendly perspective.

A High-Throughput RP-UPLC Assay for Simultaneous Determination of Telmisartan and Azelnidipine in Pharmaceutical Formulations.

Telmisartan, an angiotensin II receptor blocker, and azelnidipine, a dihydropyridine calcium channel blocker, are often co-prescribed for the effective management of hypertension. The development of accurate and efficient analytical methods is crucial for ensuring the quality control of these combination formulations. This study presents a rapid and reliable reversed-phase ultra-performance liquid chromatography (RP-UPLC) assay for the simultaneous determination of telmisartan and azelnidipine in pharmaceutical formulations. Efficient chromatographic separation was achieved on an ACQUITY BEH C18 column (100mm × 2.1mm, 3µm) using an isocratic mobile phase of pH 4.0 ammonium acetate buffer and acetonitrile (75:25% v/v) at a flow rate of 0.5mL/min. Detection was performed at 260nm, with telmisartan and azelnidipine eluting at 1.833 and 3.583 min, respectively. The method demonstrated good efficiency and minimal tailing (<1.5). Validation parameters, including accuracy, precision, linearity, specificity, and sensitivity, were determined according to International Council for Harmonisation guidelines. Calibration curves for both analytes exhibited excellent linearity (correlation coefficients > 0.999) over a concentration range of 50-150%. Recoveries from tablet dosage forms ranged from 98.0% to 102.0%, with assay values falling within the prescribed range. This validated that reversed-phase ultra-performance liquid chromatography assay offers a high-throughput approach suitable for routine quality control analysis of telmisartan and azelnidipine in pharmaceutical formulations.

Bioequivalence and Food Effect Assessment of Two Fixed-Dose Combination Formulations of Telmisartan-Hydrochlorothiazide Tablets in Chinese Healthy Subjects.

This study assessed the bioequivalence and food effect of two fixed-dose combination (FDC) formulations of telmisartan-hydrochlorothiazide tablets (telmisartan 40 mg, hydrochlorothiazide 12.5 mg) in healthy Chinese subjects. Seventy-two subjects were enrolled and divided into fasted and fed cohorts in a single-center, randomized, open-label, single-dose, three-period, three-sequence, and crossover study. The pharmacokinetic characteristics of telmisartan and hydrochlorothiazide, including Cmax and AUC, were compared after subjects received single oral doses of telmisartan-hydrochlorothiazide tablets using a validated LC-MS/MS method. Safety and tolerability of treatments were monitored. Pharmacokinetic profiles of two FDC telmisartan-hydrochlorothiazide tablets were comparable after single-dose administration. 90% CI of geometric mean ratios (GMRs) of AUC0-t, AUC0-∞, and Cmax of telmisartan and hydrochlorothiazide of two FDC formulations fell within the predefined bioequivalence range of 80.0%-125.0% under both fasted and fed conditions. Administration with food had significant effects on telmisartan pharmacokinetic parameters but a slight impact on hydrochlorothiazide. Notably, Cmax and AUC of telmisartan were significantly decreased by 39.6%-43.7% in the fed versus fasted conditions. Safety assessments revealed all treatments were safe and well tolerated. Two telmisartan-hydrochlorothiazide FDC formulations were bioequivalent in healthy Chinese subjects in both fasted and fed states. All treatments were well tolerated.

Association of once-daily single-device dual bronchodilators with prevention of rehospitalization for chronic obstructive pulmonary disease: A retrospective national inpatient database study.

Association of once-daily single-device dual bronchodilators with prevention of rehospitalization for chronic obstructive pulmonary disease: A retrospective national inpatient database study.

Mannitol-leucine synergy in nanocrystal agglomerates for enhanced systemic delivery of inhaled ketoprofen: Pharmacokinetics and safety in ovalbumin-sensitized rats.

Mannitol-leucine synergy in nanocrystal agglomerates for enhanced systemic delivery of inhaled ketoprofen: Pharmacokinetics and safety in ovalbumin-sensitized rats.

Rationale and Design of a Phase 3 Open-label Extension Study of Fixed Dose Combination of Aroxybutynin and Atomoxetine (AD109) in Obstructive Sleep Apnea

Rationale and Design of a Phase 3 Open-label Extension Study of Fixed Dose Combination of Aroxybutynin and Atomoxetine (AD109) in Obstructive Sleep Apnea

Comprehensive review of analytical techniques for evaluating fixed-dose combinations containing timolol

Comprehensive review of analytical techniques for evaluating fixed-dose combinations containing timolol

Long-Term Safety and Efficacy of the Fixed-Dose Combination of Pertuzumab and Trastuzumab for Subcutaneous Injection in Patients With HER2-Positive Early Breast Cancer in PHranceSCa, a Randomized, Open-Label Phase II Study

Long-Term Safety and Efficacy of the Fixed-Dose Combination of Pertuzumab and Trastuzumab for Subcutaneous Injection in Patients With HER2-Positive Early Breast Cancer in PHranceSCa, a Randomized, Open-Label Phase II Study

Treatment options to support the elimination of hepatitis C: an open-label, factorial, randomised controlled non-inferiority trial.

WHO recommends treating hepatitis C infection with one of three antiviral combinations for 8-12 weeks. No randomised trials have compared these regimens, and high cure rates might be achievable with shorter durations of therapy. We aimed to compare sofosbuvir-daclatasvir with sofosbuvir-velpatasvir, and to evaluate potential novel treatment strategies. We conducted a multi-arm, open-label, randomised controlled non-inferiority trial in two public hospitals in Viet Nam. Adults (aged ≥18 years) with chronic hepatitis C infection and mild-to-moderate liver fibrosis were eligible. Recruitment was stratified by centre and viral genotype (1-5 vs 6) with 1:1 random allocation to an oral fixed-dose combination of sofosbuvir 400 mg plus daclatasvir 60 mg (sofosbuvir-daclatasvir) or sofosbuvir 400 mg plus velpatasvir 100 mg (sofosbuvir-velpatasvir). Participants were simultaneously factorially randomly assigned to one of four treatment strategies: 12 weeks' standard of care (SOC); 4 weeks' therapy with four weekly PEGylated interferon alfa-2a subcutaneous injections; induction and maintenance therapy with 2 weeks' standard therapy followed by 10 weeks' therapy 5 days a week; and response-guided therapy (RGT) for 4, 8, or 12 weeks determined by viral load on day 7. The primary outcome was sustained virological response (SVR) 12 weeks after treatment completion, analysed in all evaluable participants regardless of actual treatment received. We chose a 5% non-inferiority margin for the drug comparison, and a 10% non-inferiority margin for the treatment strategy comparisons. Safety was assessed in all randomised participants. This trial is registered with ISRCTN, 61522291, and is completed. Between June 19, 2020, and May 10, 2023, 624 participants were randomised (470 [75%] were male and 154 [25%] were female). 296 (47%) had genotype 6 and 328 (53%) had genotypes 1-5. The primary outcome was assessable in 609 (98%) participants. SVR occurred in 294 (97%) of 302 participants in the sofosbuvir-daclatasvir group and 292 (95%) of 307 participants in the sofosbuvir-velpatasvir group (risk difference 2·2%, 90% credible interval [CrI] -0·2 to 4·8, within the 5% non-inferiority margin; 93% probability that sofosbuvir-daclatasvir is superior to sofosbuvir-velpatasvir). SVR occurred in 148 (99%) of 150 in the SOC group, 143 (94%) of 152 in the 4-week antiviral plus interferon group (-4·5%, 90% CrI -8·3 to -1·3), 151 (99%) of 152 in the induction-maintenance group (0·6%, -1·1 to 2·7), and 144 (93%) of 155 in the RGT group (-5·7%, -9·6 to -2·3); all risk differences were within the 10% non-inferiority margin. Serious adverse events were rare (11 [4%] of 313 participants in the sofosbuvir-velpatasvir group vs six [2%] of 311 in the sofosbuvir-daclatasvir group; risk difference -1·6% [95% CrI -4·2 to 0·8]) with no evidence of differences between regimens or strategies, but adverse reactions were very common in the 4-week antiviral plus interferon group compared with the other treatment strategies (risk difference vs SOC group, 66·8% [59·2 to 74·0]; p<0·0001). Sofosbuvir-daclatasvir was non-inferior to sofosbuvir-velpatasvir. High efficacy was seen with novel strategies, which might help to inform approaches to treatment for harder-to-reach populations. Wellcome Trust.

Efficiency of fixed-dose combinations of statin and ezetimibe in the treatment of hypercholesterolemia

Efficiency of fixed-dose combinations of statin and ezetimibe in the treatment of hypercholesterolemia