Tablet Formulation Research Articles

A study on red potato peel (Solanum tuberosum L. cv. Red Holland): characterization, composition and formulation of tablet using different drying techniques

A study on red potato peel (Solanum tuberosum L. cv. Red Holland): characterization, composition and formulation of tablet using different drying techniques

Applying Box-Behnken Design in Herbal Product Development: Semha-Pinas Plain Tablets

Phlegm production is a common symptom of upper respiratory tract infections and some allergies. A traditional Thai herbal formula called Semha-Pinas offers an alternative treatment option for managing this symptom. This study aimed to optimize the formulation of Semha-Pinas plain tablets using the Box-Behnken design. Three factors were identified as potentially influencing tablet properties: compressional force, quantity of spray-dried lactose, and quantity of croscarmellose sodium. Initial screening with a one-factor-at-a-time approach helped narrow down the relevant ranges for each factor. Subsequently, the Box-Behnken design was employed with compressional forces ranging from 1,500 to 2,500 psi, spray-dried lactose quantities from 0 to 10%, and croscarmellose sodium quantities from 2 to 4%. Results showed that the optimal formulation, achieving a hardness of 5 to 8 kP, disintegration time of at least 0.5 minutes, and friability of not more than 0.4%, was found at 1,500 psi compressional force, 6% spray-dried lactose, and 3% croscarmellose sodium. This optimized formulation exhibited the following characteristics: tablet weight of 381.23 ± 0.80 mg, diameter of 9.66 ± 0.01 mm, thickness of 4.20 ± 0.04 mm, hardness of 7.50 ± 0.41 kP, disintegration time of 0.67 ± 0.07 minute, and friability of 0.22% ± 0.04%. Verification data confirmed the accuracy of the predictions, with all percent errors falling below 10%. In conclusion, this study successfully applied the Box-Behnken design to develop Semha-Pinas plain tablets that meet the relevant pharmacopoeial criteria.

FORMULATION AND CHARACTERIZATION EFFERVESCENT TABLETS OF GAMBIER LEAF EXTRACT (Uncaria gambier Roxb)

Background: Gambier, also known as the term (Uncaria gambier Roxb), is a plant that has long been cultivated in Indonesia. The components of flavonoid compounds in gambier plants have been widely reported as antioxidants. Using the gambier plant will be more accessible and more practical if it is made in dosage form, one of which is in the form of effervescent tablets. Objective: To determine the physical and chemical characteristics of effervescent tablets of gambier leaf extract (Uncaria gambier Roxb). Methods: Descriptive design, which includes phytochemical screening research, extract quality test, physical and chemical characteristics test of effervescent tablets formulation. Results: Positive gambier leaf extracts contain flavonoid compounds, alkaloids, tannins, and saponins. The average weight uniformity test of the tablet is 1.57 ± 0.02 grams, the average tablet thickness test of the tablet is 0.5±0 cm while a tablet's average diameter is 1.6±0 cm, the fragility test obtained <1%, the average hardness test of the tablet is 4.34±0.02 kg, the solubility time of the tablet obtaining is 1.6 ±0.4 minutes and tablets pH is 5.5±0.2. Conclusion: It is possible to draw the conclusion that the positive gambier leaf extract includes flavonoid components, alkaloids, tannins, and saponins based on the findings of the data previously gathered. The quality test of gambier leaf extract is already qualified, and the test of the characteristics of the physical and chemical properties produced is suitable based on Pharmacopeia Indonesia Standard. Keywords: Gambier; Extract; Tablet Effervescent

Breast cancer survivors’ opinion on personalizing endocrine therapy and developing informative tools

Understanding breast cancer survivors’ perspectives is critical to personalizing endocrine therapy (ET) in the adjuvant setting. A nationwide survey among breast cancer survivors was proposed in France, in collaboration with patient advocacy organizations, to assess their perspectives on personalizing ET and developing dedicated informative tools. This survey explored patients’ preferences regarding ET intake schedule, formulation, presentation (color, taste, shape, size, design, and packaging), combination with agents targeting ET-related adverse events, and a mobile application to support them during ET. Of the 1103 individuals who started the survey, 939 (85.1%) were eligible for enrollment and completed the survey. The majority of the participants considered that a personalized ET should take into consideration the intake schedule (n = 974, 90.7%) and swallowable tablet formulation (n = 606, 64.5%), without a preference for ET presentation (n = 619; 65.9%). The majority of the participants expressed a willingness to participate in a potential clinical trial evaluating the combination of ET with agents targeting ET-related adverse events at the start of ET (n = 752, 80.1%) or in the case of major ET-related adverse events (n = 778, 82.8%). The primary considerations were to have an uncompromised ET efficacy and a guaranteed reduction of adverse events. Last, a dedicated mobile application was considered helpful by 665 participants (70.8%). Informative tools should focus on the recommendations for dealing with adverse events (n = 593, 63.2%), the impact on the patient’s daily life (n = 515, 54.9%), benefits (n = 504, 53.7%), and adverse events (n = 494, 52.6%) of ET. This survey paves the way for multimodal strategies that can include a personalized ET (e.g., ET in combination with agents targeting ET-related adverse events) and dedicated mobile applications to ultimately improve adherence.

Preferences and perceptions of 617 migraine patients on acute and preventive migraine treatment attributes and clinical trial endpoints

ABSTRACT Background To identify the preferences and perceptions of migraine patients for acute and preventive treatment options and to investigate which treatment outcomes are the most important. Design and Methods The authors performed a choice-format survey in a cohort of migraine patients from Greece and Cyprus. A self-administered questionnaire developed in collaboration with the Greek Society of Migraine Patients was used. Results Questionnaires were collected from 617 migraine patients. Efficacy was preferred over safety as the single most important parameter, both in acute and preventive treatment. When analyzing single outcomes, patients prioritized a complete pain remission at 1-hour post-dose for acute therapies. Regarding migraine prevention, a 75% reduction in frequency, intensity of pain, accompanying symptoms and acute medication intake were considered as most important. Conversely, outcomes routinely used in clinical trials, namely complete or partial pain remission at 2-hours post-dose for acute treatment and 50% or 30% reduction in migraine frequency for prevention, were not deemed particularly relevant. Tablet formulation was mostly preferred, both in acute and preventive treatment. Conclusion: Listening to patients’ needs may add a piece of the puzzle that is generally missing in clinical practice and often explains the lack of adherence in both acute and preventative anti-migraine therapies.

Development of the optimal composition of tablets with the active substance potassium 2-((4-amino-5-(morpholinomethyl)-4H-1,2,4-triazol-3-yl)thio)acetate. Message 1. Study of the effect of auxiliary substances on bulk density, bulk density after shrinkage, fluidity and angle of natural slope of powder masses

The pharmaceutical industry continually evolves to meet the demands of modern society for high-quality medications. One avenue of this advancement involves exploring new technologies for manufacturing tablet formulations that adhere to contemporary quality standards. An integral aspect of this process is the careful selection of optimal excipients that preserve the pharmacological activity of the active substance to the greatest extent possible. Investigating the impact of various excipients on the tablet compression process is pivotal to addressing this challenge. Therefore, the study of the influence of excipients on the pharmaco-technological properties of tablets with potassium 2-((4-amino-5-(morpholinomethyl)-4H-1,2,4-triazol-3-yl)thio)acetate is an important aspect, so as this substance has pronounced hepatoprotective and antioxidant properties. The aim of the work was to study the effect of excipients on the pharmaco-technological parameters of tablets with the active ingredient potassium 2-((4-amino-5-(morpholinomethyl)-4H-1,2,4-triazol-3-yl)thio)acetate obtained by the method direct pressing. Materials and methods. Active substance – potassium 2-((4-amino-5-(morpholinomethyl)-4H-1,2,4-triazol-3-yl)thio)acetate, auxiliary substances (excipients based on microcrystalline cellulose, auxiliary substances based on granulated sugars, lubricants, lubricants). The powder mixtures were checked for bulk density, bulk density after compaction, flowability and angle of natural slope. The tablets were pressed by the direct pressing method. The effect of auxiliary substances on the pressing process was studied. Results. The conducted studies show that the powder mass of potassium 2-((4-amino-5-(morpholinomethyl)-4H-1,2,4-triazol-3-yl)thio)acetate and auxiliary substances was characterized by good pharmaco-technological indicators – bulk density and bulk density after compaction, fluidity and angle of natural slope. Further, during the tableting process, it was confirmed that the powder mass has satisfactory properties. In almost all series of experiments, the process of pressing the tablets took place without difficulties, the matrix was evenly filled, but the force of pushing the tablets out of the matrix was different. Conclusions. The study involving 16 excipients, including fillers, disintegrants, and lubricants to develop the composition and technology was conducted of a new tablet medicine containing potassium 2-((4-amino-5-(morpholinomethyl)-4H-1,2,4-triazole-3-yl)thio)acetate. This comprehensive examination enabled us to identify the optimal auxiliary substances that fulfill all the pharmaco-technological requirements stipulated by the State Pharmacopoeia of Ukraine for tablet formulations.

Formulation and Evaluation of Kuberaksha Tablet in the Treatment of Udavartini Yonivyapada (Primary Dysmenorrhoea)

Formulation and Evaluation of Kuberaksha Tablet in the Treatment of Udavartini Yonivyapada (Primary Dysmenorrhoea)

Synthesis, Characterization, and Stability Optimization of Ibuprofen Cocrystals eEploying Various Hydrophilic Polymers.

Cocrystals are an efficient way for the delivery of low soluble drugs but when dissolved they rapidly disproportionate. To formulate the cocrystals in tablets, cocrystals must be stabilized. In this study ibuprofen-nicotinamide (IBU-NIC) cocrystals were synthesized initially by slow solvent evaporation and for bulk production by fast solvent evaporation techniques. The cocrystals were characterized by powder X-ray diffraction (PXRD), Fourier transform infrared spectrophotometer (FTIR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and optical microscopy. The ibuprofen cocrystals showed greater solubility compared to the parent drug. Intrinsic dissolution data was utilized for efficacious screening of tablet formulations. Using hydrophilic polymers at a ratio of 6:1 (polymer to IBU-NIC cocrystal ratio), hydroxypropyl methylcellulose (F1), polyvinylpyrrolidone (PVP) K-30 (F2) and PVP K-90 (F3), three tablet formulations were prepared that stabilized cocrystals during dissolution. The drug release profiles after 60 minutes from formulations F1 (92.30), F2 (98.54), F3 (99.88) were all higher compared to the marketed brand BRUFEN® F, (79.61%) in a simulated intestinal media (p<0.001). Significant increase in the dissolution rate of cocrystal was observed with no phase change in all formulations.

KRYSTAL-12: Phase 3 study of adagrasib versus docetaxel in patients with previously treated advanced/metastatic non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation.

LBA8509 Background: Adagrasib (ADA) is a potent covalent inhibitor of KRASG12C with favorable properties such as long half-life (23 h), dose-dependent pharmacokinetics, and brain penetrance. In the phase 1/2 KRYSTAL-1 trial, ADA demonstrated deep and durable responses with promising PFS and OS in patients (pts) with previously treated KRASG12C-mutated NSCLC. Here, we report the primary analysis from KRYSTAL-12 (NCT04685135), a randomized, open-label phase 3 trial of ADA compared with docetaxel (DOCE) in pts with KRASG12C-mutated locally advanced or metastatic NSCLC who had previously received a platinum-based chemotherapy, concurrently or sequentially with anti-PD-(L)1 therapy. Methods: Pts with KRASG12C-mutated locally advanced or metastatic NSCLC, previously treated with platinum-based chemotherapy and anti-PD-(L)1 therapy, were randomized 2:1 (stratified by region [non-Asia Pacific vs Asia Pacific] and sequential vs concurrent chemoimmunotherapy) to receive ADA (600 mg BID orally; tablet formulation) or DOCE (75 mg/m2 Q3W IV), with the ability to crossover to ADA upon disease progression (assessed by real-time blinded independent central review [BICR]). No washout period was required between prior anti-PD-(L)1 therapy and study treatment. Primary endpoint was PFS assessed per BICR according to RECIST v1.1. Secondary endpoints included ORR by BICR, duration of response (DOR), OS, 1-year OS rate, and safety. Results: In total, 301 pts were randomized to ADA and 152 to DOCE. Baseline characteristics were generally similar between treatment arms. With a median follow-up of 9.4 mo (data cutoff 31 Dec, 2023), the primary endpoint of PFS was significantly improved with ADA over DOCE (HR 0.58 [95% CI, 0.45–0.76]; P &lt; 0.0001; median PFS 5.49 vs 3.84 mo). ORR by BICR was also significantly higher with ADA compared with DOCE (31.9% [95% CI, 26.7–37.5] vs 9.2% [95% CI, 5.1–15.0]; odds ratio 4.68 [95% CI, 2.56–8.56]; P &lt; 0.0001); median DOR was 8.31 (95% CI, 6.05–10.35) vs 5.36 (95% CI, 2.86–8.54) mo, respectively. Treatment-related adverse events (TRAEs) were reported in 94.0% of pts treated with ADA and 86.4% with DOCE; grade ≥3 TRAEs occurred in 47.0% and 45.7% of pts, respectively. TRAEs led to discontinuation of ADA in 7.7% of pts and DOCE in 14.3%. Additional efficacy and safety analyses, including subgroup analyses, will be presented. Conclusions: In the phase 3 KRYSTAL-12 trial, ADA demonstrated a statistically significant and clinically meaningful improvement in PFS and ORR over DOCE in pts with previously treated KRASG12C-mutated NSCLC. Safety profile of ADA was consistent with previous reports and with no new safety signals. These results further support ADA as an efficacious treatment option for pts with previously treated KRASG12C-mutated locally advanced or metastatic NSCLC. Funding: Mirati, a Bristol Myers Squibb Company. Acknowledgements: KRYSTAL-12 was sponsored by Mirati, a Bristol Myers Squibb Company. Third-party medical writing support, under the direction of the authors, was provided by Flaminia Fenoaltea, MSc, of Ashfield MedComms, an Inizio company, and was funded by Mirati, a Bristol Myers Squibb Company. Clinical trial information: NCT04685135 .

Pharmacokinetics and Bioequivalence of Vardenafil Hydrochloride in Healthy Chinese Volunteers.

Vardenafil hydrochloride tablet is an inhibitor of phosphodiesterase type 5, primarily for the treatment of erectile dysfunction. This postprandial study evaluated the pharmacokinetics and bioequivalence of the test and reference formulations of vardenafil hydrochloride tablets in healthy Chinese volunteers. An open, randomized, single-center, single-dose, 2-period, 2-sequence bioequivalence test was conducted on 66 healthy subjects under fed conditions. Subjects were randomly assigned to a 20-mg test or reference formulation with a 7-day washout period. Venous blood samples (4mL) were collected from each subject 25 times spanning predose (0hour) to 24hours after dosing. The plasma concentration of vardenafil was determined by high-performance liquid chromatography-tandem mass spectrometry. Sixty-two volunteers completed the study. Under fed conditions, the maximum plasma concentration was 29.1ng/mL, the area under the concentration-time curve (AUC) from time 0 to the time of the last measurable concentration was 85.3ng•h/mL, and AUC from time 0 to infinity was 87.1ng•h/mL. The 90% confidence intervals of the geometric mean ratio of AUC time 0 to the time of the last measurable concentration and AUC from time 0 to infinity were within the bioequivalence acceptance range of 0.80-1.25. The test formulation was a bioequivalent alternative to the reference formulation when taken under fed conditions in healthy Chinese subjects.

A Comprehensive Study for Assessing the Demand and Supply Dynamics of Parkinson's Disease Medication in Roorkee, Uttarakhand

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta region of the midbrain. This depletion of dopamine, a neurotransmitter crucial for regulating movement, leads to the characteristic motor symptoms of PD, including tremors, rigidity, bradykinesia, and postural instability. In India, the prevalence of PD is increasing, necessitating greater attention to the availability and distribution of appropriate medication. This comprehensive study aims to assess the demand and supply dynamics of PD medication in Roorkee, Uttarakhand. After recording the sales per week of various drugs, brands, dosage forms, and strengths available in Roorkee, it was determined that SINEMET (Carbidopa + Levodopa) is widely accessible in the region, with STALEVO, MIRAPEX (Pramipexole), and ARTANE (Trihexyphenidyl) being the other prominent brands available in local medical stores. These medications are primarily in tablet form. Sales data from different stores indicated that SINEMET (Carbidopa + Levodopa 25/250 mg) is the most popular drug in the Roorkee area for treating PD. In terms of drug type analysis, levodopa-based decarboxylase inhibitors, particularly the combination of Levodopa and Carbidopa, currently hold a dominant position in the PD drug market in the region

Calorimetric investigation on heat release during the disintegration process of pharmaceutical tablets

The compendial USP〈701〉 disintegration test method offers a crucial pass/fail assessment for immediate release tablet disintegration. However, its single end-point approach provides limited insight into underlying mechanisms. This study introduces a novel calorimetric approach, aimed at providing comprehensive process profiles beyond binary outcomes. We developed a novel disintegration reaction calorimeter to monitor the heat release throughout the disintegration process and successfully obtained enthalpy change profiles of placebo tablets with various porosities. The formulation comprised microcrystalline cellulose (MCC), anhydrous lactose, croscarmellose sodium (CCS), and magnesium stearate (MgSt). An abrupt temperature rise was observed after introducing the disintegration medium to tablets, and the relationship between the heat rise time and the tablet’s porosity was investigated. The calorimeter’s sensitivity was sufficient to discern distinct heat changes among individual tablets, and the analysis revealed a direct correlation between the two. Higher porosity corresponded to shorter heat rise time, indicating faster disintegration rates. Additionally, the analysis identified a concurrent endothermic process alongside the anticipated exothermic phenomenon, potentially associated with the dissolution of anhydrous lactose. Since lactose is the only soluble excipient within the blend composition, the endothermic process can be attributed to the absorption of heat as lactose molecules dissolve in water. The findings from this study underscore the potential of utilising calorimetric methods to quantify the wettability of complex compounds and, ultimately, optimise tablet formulations.

Community-acquired pneumonia in outpatients: topical issues of antibacterial therapy

Community-acquired pneumonia (CAP) is one of the leading causes of morbidity and mortality worldwide. Successful treatment of patients with CAP is mainly determined by the correct choice of the place of treatment (outpatient or inpatient) and the correct initial empirical therapy, considering the predictable spectrum of potential pathogens of CAP. The article provides up-to-date data on the etiological structure of non-severe CAP. Most patients with CAP receive outpatient medical care, which is determined by their clinical status and a limited number of laboratory data for minimizing the risk of adverse outcomes in CAP. The absence of a microbiological diagnosis in a mild course of CAP does not lead to a decrease in the effectiveness of empirical antibacterial therapy in outpatient settings. The article highlights current clinical recommendations on the choice of empirical antibiotic therapy for CAP in outpatients. Amoxicillin is a semi-synthetic penicillin, which, including in combination with the beta-lactamase inhibitor clavulanic acid, is the most affordable and widely used penicillin in various countries. According to clinical recommendations, amoxicillin, including in combination with a β-lactamase inhibitor, is the drug of choice for the initial empirical therapy of most outpatients with CAP. The oral route is the most common and preferred for antibiotic delivery in mild CAP. Dispersible forms of tablets have certain advantages, including easier intake in patients with difficulty swallowing, such as the elderly, stroke patients, and children. The assessment of biological equivalence showed similar pharmacokinetic parameters of Amoxicillin and Amoxicillin in combination with clavulanic acid in the form of dispersible tablets and in the original form of film-coated tablets.

LIBS as diagnostics of analytical chemistry for surface mapping of complex mixed samples simulating debris inside the TEPCO's Fukushima Daiichi Nuclear Power Plant (FDNPS) reactor cores

The Nuclear Energy Agency (NEA) launched the Nuclear Education, Skills and Technology (NEST) Framework to pursue careers in the nuclear field, by exposing researcher working on these topics to international challenging project of real-world issue and by transferring the knowledge and expertise accumulated in the current generation to them through hands-on training.In this framework the 2022 edition of the NEST project offered a training educational period at the Collaborative Laboratories for Advanced Decommissioning (CLADS) located at Tomioka, Futaba District, in the Fukushima prefecture (Japan).Among the research sectors active at CLADS there is the application and development of the LIBS technique as diagnostics of analytical chemistry aiming at characterizing the debris inside the Tokyo Electric Power Company (TEPCO)’s FDNPS reactor cores after the tsunami of March 2011, which destroyed three of the six reactors of the plant. These debris need to be chemically characterized with techniques suitable to be implemented in compact, remote and radiation resistant devices, due to the residual radioactivity of the cores. The present study shows the results in realizing chemical bi-dimensional maps of samples in the form of compressed tablets of mixed oxides, with a complex distribution and concentration of chemicals simulating these debris. The results allowed to create detailed maps of the samples, with spatial resolution down to 0.5 mm and an excellent correspondence between the real spatial distribution of the materials and that reconstructed by LIBS.Moreover, it was found a good correspondence between the nominal concentration of the chemicals and the concentration estimated by using LIBS.This study shows the potentialities of LIBS in the realization of chemical maps on samples of interest for FDNPS, providing multi-elemental images of the samples under analysis.

Pharmacokinetics and Bioequivalence of Two Formulations of Azithromycin Tablets: A Randomized, Single-Dose, Three-Period, Crossover Study in Healthy Chinese Volunteers Under Fasting and Fed Conditions.

Azithromycin is the first azalide antibiotic that is related to the macrolide family of antibiotics. Bioequivalence studies in China are initiated by the National Medical Products Administration (NMPA), which supports a generic consistency evaluation program for ensuring that generic products manufactured in China meet the required standards and provide equivalent therapeutic effects to their reference products. This study aimed to assess the bioequivalence of two azithromycin tablets under both fasting and fed conditions in healthy Chinese volunteers. This was a single-center, open-label, single-dose, randomized, three-way crossover trial with two independent groups (fasting group and fed group). A total of 72 healthy Chinese subjects (36 subjects in the fasting state and 36 subjects in the fed state) were enrolled and randomized to treatment. Blood samples were collected from 0 to 120 h after a single oral dose of a 250-mg generic azithromycin tablet (test, T) or branded azithromycin tablet (reference, R). The plasma concentrations of azithromycin were determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC‒MS/MS). A non-compartmental analysis method was used to estimate the pharmacokinetic parameters. Adverse events were documented. In a fasting state, the bioequivalence of maximum plasma concentration (Cmax) was evaluated using the reference-scaled average bioequivalence (RSABE) approach (within-subject standard deviation, SWR >0.294), and the bioequivalence of area under the concentration-time curve from time 0 to the time of the last measurable plasma concentration (AUC0-t) and area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-∞) were evaluated by the average bioequivalence (ABE) method (SWR < 0.294). The geometric mean ratio (GMR) of T/R for Cmax was 106.49%, while the 95% upper confidence bound was < 0. The GMRs of AUC0-t and AUC0-∞ were 103.34% and 101.28%, and the 90% confidence intervals (CIs) of the test/reference were 95.90-111.35%/94.85-108.15%, respectively. In the fed state, the RSABE approach was applied to estimate the bioequivalence of Cmax (SWR >0.294), and the ABE approach was applied to estimate the bioequivalence of AUC0-t and AUC0-∞ (SWR < 0.294). The GMR for Cmax was 99.80%, while the 95% upper confidence bound value was < 0. The GMRs of AUC0-t and AUC0-∞ were 97.07% and 98.15%, and the 90% CIs of the T/R were 90.02-104.68% and 90.66-106.25%, respectively. All adverse events were mild and transient. The trial indicated that the test and the reference azithromycin tablets were bioequivalent and well tolerated in healthy Chinese volunteers under both fasting and fed conditions. Clinicaltrials, ChiCTR2300071630 (retrospectively registered in 19/05/2023).

Pharmacokinetics and bioequivalence study of candesartan cilexetil tablet in Chinese volunteers under fasting condition: an open-label, randomized-sequence, 2-period crossover study.

Candesartan is an antihypertensive agent that acts on an angiotensin II receptor. Candesartan cilexetil is a prodrug that is converted into the active form of candesartan during intestinal absorption. This study aimed to assess the pharmacokinetics and bioequivalence of a reference and a test formulation of candesartan cilexetil tablets in healthy Chinese volunteers. A randomized, open-label, single-dose, crossover study was conducted with two treatment periods. Forty-eight healthy Chinese volunteers participated under fasted conditions. Qualified subjects were randomly divided into two groups (1:1 ratio) to receive either the test or reference formulation first. A washout period of 14 days separated the administration of the two formulations. Blood samples were collected at specific time points and analyzed for candesartan concentration using Ultra High-Performance Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS/MS). The maximum concentration (Cmax), the AUC from time zero to the last measured time point (AUC0-t) and the AUC from time zero to infinity (AUC0-∞) fell within the bioequivalence range of 80% to 125%. These results suggest that the test and reference formulations of candesartan cilexetil tablets are bioequivalent, meaning they have similar rates and extents of absorption in healthy Chinese volunteers. No serious adverse events or side effects were reported throughout the study.

Enhancing drug administration flexibility: evaluation of pharmacokinetic properties of tegoprazan orally disintegrating tablet (ODT) administered via nasogastric tube or oral dosing.

Tegoprazan orally disintegrating tablet (ODT) formulation is a novel formulation to improve a convenience in comparison to taking the conventional tablet of tegoprazan, a potassium-competitive acid blocker. The purpose of this study was to evaluate the pharmacokinetic and safety profiles of tegoprazan ODT when administered via two routes: nasogastric tube or oral dosing. This study is expected to expand the administration route of tegoprazan ODT. The study was conducted in an open-label, randomized, single-dose, two-way crossover design with a 1-week washout period. Healthy subjects aged 19 to 45 years were administered 50 mg of tegoprazan ODT orally or dissolved in water via nasogastric tube. Tegoprazan, the active ingredient, was quantified using a ultra-high performance liquid chromatography tandem mass spectroscopy (UPLC-MS/MS), and pharmacokinetic parameters were determined through non-compartmental analysis. Safety was monitored throughout the study. A total of 48 subjects, successfully completed the trial. The geometric mean ratios for log-transformed Cmax and AUCt, representing the ratio of nasogastric tube group to oral dosing group, along with 90% confidence intervals, were 1.1087 (1.0243-1.2000) and 1.0023 (0.9620-1.0442), respectively. All adverse events were unrelated to tegoprazan and mild in intensity. The pharmacokinetic profiles of tegoprazan ODT were equivalent between the nasogastric tube and oral administration. Considering the demonstrated linear pharmacokinetics and concentration-dependent pharmacodynamics of tegoprazan, the administration via nasogastric tube is expected to yield effects equivalent to those of oral administration. This approach offers a viable alternative, especially beneficial for patients with oral intake difficulties.

ReNeu: A pivotal phase 2b trial of mirdametinib in children and adults with neurofibromatosis type 1 (NF1)-associated symptomatic inoperable plexiform neurofibroma (PN).

3016 Background: PN in patients (pts) with NF1 can cause pain, disfigurement, impaired quality of life (QoL), and can undergo malignant transformation. ReNeu (NCT03962543), a multicenter, open-label, Phase 2b study, evaluated efficacy and safety of the highly selective, oral, investigational MEK1/2 inhibitor mirdametinib in adult (≥18 y) and pediatric (2-17 y) pts with inoperable NF1 PN causing significant morbidities. Methods: Mirdametinib was administered as a capsule or dispersible tablet (2 mg/m2 BID, max 4 mg BID) without regard to food in 3 wk on/1 wk off 28-d cycles. The primary endpoint was confirmed objective response rate (ORR; percentage of pts with MRI-assessed ≥20% reduction of target PN volume by blinded independent central review [BICR] within the 24-cycle treatment phase). The minimum clinically relevant ORR (null) was defined as 23% for adults and 20% for pediatrics. Ptscould continue treatment in an optional long-term follow-up (LTFU) phase. Additional key endpoints were duration of response (DoR), time to response (TTR), change from baseline (BL) in target PN volume, pain severity (Numerical Rating Scale-11 [NRS-11]), pain interference (Pain Interference Index [PII]), health-related (HR) QoL (PedsQL), and safety. Results: All114 pts (58 adult, 56 pediatric) received mirdametinib. As of the 20 Sept 2023 data cutoff (DCO), BICR-confirmed ORR during the treatment phase was 41% (95% CI, 29-55; P&lt;.001 vs null) in adults and 52% (95% CI, 38-65; P&lt;.001 vs null) in pediatric pts. Two adult pts and 1 pediatric pt also had a confirmed response in the ongoing LTFU. Median (min, max) target PN volumetric best response from BL was -41% (-90, 13) and -42% (-91, 48) in adult and pediatric pts, respectively. As of the DCO, median treatment duration was 22 mo for each cohort and median DoR was not reached. Median (range) TTR was 7.8 (4-19) mo in adult pts and 7.9 (4-19) mo in pediatric pts. Adult and pediatric pts had statistically significant improvements from BL to cycle 13 in NRS-11, PII, and key PedsQL measures. Most frequent (≥35% pts) treatment-emergent adverse events (TEAEs) were dermatitis acneiform, diarrhea, nausea, and vomiting in adults and diarrhea, dermatitis acneiform, and vomiting in pediatric pts. 16% and 25% of adult and pediatric pts, respectively, had grade ≥3 treatment-related AEs, and 22% and 9%, respectively, discontinued due to TEAEs. Conclusions: In ReNeu, the largest multicenter NF1 PN trial reported to date, mirdametinib demonstrated a statistically significant ORR by BICR, with deep and durable PN volume reductions, significant improvements in pain severity, pain interference, and HRQoL, and a manageable safety profile in both adults and children. Together with a dispersible tablet formulation, these results underscore mirdametinib’s potential to become an important new treatment option for NF1 PN pts across all ages. Clinical trial information: NCT03962543 .

Fulvestrant with or without the cyclin-dependent kinase 7 (CDK7) inhibitor samuraciclib in advanced hormone receptor positive (HR+) breast cancer after CDK4/6 inhibition: Phase II SUMIT-BC study.

TPS1126 Background: CDK7 enhances oncogene transcription and upregulates anti-apoptotic genes, accelerates the cell cycle via CDK phosphorylation, and activates estrogen receptors (ERs) that can drive resistance to hormonal therapy in cancer. CDK7 inhibition therefore represents a potential anticancer strategy in cancer. Samuraciclib (CT7001) is a small molecule, ATP competitive, selective oral inhibitor of CDK7 that inhibits these key effects of CDK7. Samuraciclib had a favorable safety profile and showed clinical activity when combined with fulvestrant in a phase I study in patients with HR+/HER2− advanced breast cancer (BC) who had previously been treated with a CDK4/6 inhibitor. Patients with no detectable TP53 mutation in ctDNA at baseline and those without baseline liver metastases appeared to have better outcomes. The instant release capsule formulation of samuraciclib used in this study released large amounts of samuraciclib high in the gastrointestinal (GI) tract, which may have contributed to the observed low grade GI adverse events, which were managed with prophylaxis and counselling (1). Methods: A phase 2 open-label randomized study has been designed to evaluate the efficacy, safety, pharmacokinetics (PK), and quality of Life (QoL) of samuraciclib combined with fulvestrant compared to fulvestrant monotherapy (SUMIT-BC; NCT05963984). Eligible patients (n=60) are ≥18 years, have histologically or cytologically confirmed ER+/HER2− advanced or metastatic BC not amenable to resection or radiotherapy of curative intent, have received an aromatase inhibitor combined with a CDK4/6 inhibitor in the adjuvant or advanced setting, are receiving a luteinizing hormone-releasing hormone agonist if pre/perimenopausal, and have RECIST v1.1 evaluable disease. Prior SERD, mTOR inhibition, or chemotherapy for advanced BC are not permitted. All patients undergo baseline Guardant360 ctDNA analysis to establish TP53 and other mutation status. Patients are randomized 1:1:1 to fulvestrant alone (500 mg IM administered on days 1, 15 and 29 and then monthly), fulvestrant and samuraciclib 240 mg QD, or fulvestrant and samuraciclib 360 mg QD. In preparation for phase 3 development, a novel single tablet formulation of samuraciclib is used, which may enhance GI tolerability. Patients undergo RECIST v1.1 evaluation at baseline, every 8 weeks until week 48, and every 12 weeks thereafter. The primary endpoint is clinical benefit response at 24 weeks. Secondary endpoints are tolerability, progression free survival, overall response rate, duration of response, and PK of fulvestrant and samuraciclib. QoL (Functional Assessment of Cancer Therapy - Breast questionnaire [FACT-B]) and correlations between TP53 mutation and efficacy/safety will be assessed. 1. Coombes et al. Nature Comms 2023. Clinical trial information: NCT05963984 .

Analytical Method Development and Optimization on High Performance Liquid Chromatography for Related Substances Test of Gliclazide Drug as Active Pharmaceutical Ingredient

Diabetes mellitus, particularly Type 2 Diabetes Mellitus (T2DM), presents a significant global health challenge, necessitating continuous advancements in therapeutic strategies. Gliclazide, an oral selective inhibitor of sodium glucose co-transporter-2 (SGLT2), has emerged as a promising agent for managing T2DM by facilitating urinary glucose excretion and reducing plasma glucose levels. However, ensuring the quality and efficacy of pharmaceutical formulations remains crucial for regulatory approval and clinical effectiveness. In this study, we present the development of an improved stability-indicating Reverse Phase-High Performance Liquid Chromatography (RP-HPLC) method for the precise quantification of Gliclazide. The novel analytical method employs 0.1% Potassium Phosphate in water 0.1% Potassium Phosphate in methanol (MeOH) as the mobile phase, demonstrating enhanced sensitivity, cost-effectiveness, and reduced reliance on organic chemicals. Through rigorous validation following International Conference on Harmonisation (ICH) guidelines, the developed method exhibited superior performance in terms of retention times compared to existing methodologies. The proposed analytical approach holds promise for routine analysis of Gliclazide in both bulk and tablet formulations, offering a valuable tool for pharmaceutical quality control and clinical research in the management of T2DM.