Test Formulation Research Articles

Tramadol/Diclofenac Fixed-Dose Combination for Acute Pain Management: Bioavailability Assessment of a Generic Product.

The multimodal analgesia strategy for acute pain involves using 2 or more analgesic medications with distinct mechanisms of action. This study assessed the bioavailability and tolerability of 2 tramadol hydrochloride (50mg)/diclofenac sodium (50mg) fixed-dose combination formulations under fed conditions to attend the Brazilian regulatory requirements for generic product registration. An open-label, randomized, single-dose, 2-period, 2-way crossover trial was conducted, including healthy subjects of both sexes. Subjects received a single dose of either the test or reference formulation of tramadol/diclofenac fixed-dose combination tablets with a 7-day washout period. Blood samples were collected up to 36hours after dosing for tramadol and 12hours for diclofenac and quantified using a validated liquid chromatography-tandem mass spectrometry method. Of 56 subjects enrolled, 53 completed the study. The 90% confidence intervals for maximum plasma concentration and area under the concentration-time curve from time 0 to the last quantifiable concentration were within acceptable bioequivalence limits of 80%-125%. Considering the results presented in this study, the test formulation is bioequivalent to the reference formulation and could be interchangeable in medical practice.

In Vitro In Vivo Extrapolation and Bioequivalence Prediction for Immediate-Release Capsules of Cefadroxil Based on a Physiologically-Based Pharmacokinetic ACAT Model.

Physiologically based pharmacokinetic (PBPK) modeling is a mechanistic concept, which helps to judge the effects of biopharmceutical properties of drug product such as in vitro dissolution on its pharmacokinetic and in vivo performance. With the application of virtual bioequivalence (VBE) study, the drug product development using model-based approach can help in evaluating the possibility of extending BCS-based biowaiver. Therefore, the current study was intended to develop PBPK model as well as in vitro in vivo extrapolation (IVIVE) for BCS class III drug i.e. cefadroxil.A PBPK model was created in GastroPlus™ 9.8.3 utilizing clinical data of immediate-release cefadroxil formulations. By the examination of simulated and observed plasma drug concentration profiles, the predictability of the proposed model was assessed for the prediction errors. Furthermore, mechanistic deconvolution was used to create IVIVE, and the plasma drug concentration profiles and pharmacokinetic parameters were predicted for different virtual formulations with variable cefadroxil in vitro release. Virtual bioequivalence study was also executed to assess the bioequivalence of the generic verses the reference drug product (Duricef®).The developed PBPK model satisfactorily predicted Cmax and AUC0-t after cefadroxil single and multiple oral dose administrations, with all individual prediction errors within the limits except in a few cases. Second order polynomial correlation function obtained accurately predict in vivo drug release and plasma concentration profile of cefadroxil test and reference (Duricef®) formulation. The VBE study also proved test formulation bioequivalent to reference formulation and the statistical analysis on pharmacokinetic parameters reported 90% confidence interval for Cmax and AUC0-t in the FDA acceptable limits.The analysis found that a validated and verified PBPK model with a mechanistic background is as a suitable approach to accelerate generic drug development.

DESIGN, DEVELOPMENT AND IMPROVEMENT OF AN EMULGEL CONTAINING SILVER NANOPARTICLES AND VITAMIN D-3 FOR ITS POTENTIAL TO ACCELERATE THE HEALING OF WOUND

Objective: The aim of this research work was to prepare a topical emulgel based dosage form incorporated with vitamin D-3 and silver nanoparticles to reduce the wound healing time in any kind of wound. Methods: Central Composite Design (CCD) was applied for the optimization of emulgel by using Design expert software. Three responses (pH, viscosity, and in vitro drug release) and two factors (Carbopol concentration and stirring duration) were chosen, and Statistical Analysis of Variance (ANOVA) revealed that all the factors were significantly affecting the responses. Silver Nanoparticles (SNPs) was prepared with Green Tea Extract (GTE) and evaluated for particle size, Poly Dispersity Index (PDI), zeta potential and Fourier Transform Infra-red (FTIR) spectroscopy and revealed that SNPs of desired range and stability have been synthesized. Here excision wound model was used to evaluate the wound healing activity of formulation in vivo. Results: Maximum in vitro release 88.2±2.1 has shown by the optimized formulation F13, pH and viscosity were also found in optimum range i.e., 6.2±0.4 and 1672±33 respectively, followed by Korsmeyer and Peppas model. Total eight groups were designed for animal study and silver sulphadiazine was used as marketed formulation. F13 formulation was further evaluated for in vivo data, it was revealed that emulgel loaded with high dose of vitamin D-3 along with silver nanoparticles has shown 100.5±1.7% wound contraction, while marketed formulation has shown 103.7±1.1% wound contraction, which was much similar with test formulation. Cytotoxic cell study was done using assay on chicken egg, formulation has not shown any cytotoxic behaviour like haemolysis and cell damage on chick embryo’s blood vessels. Accelerated stability study of the optimized formulation was also performed to check whether the formulation was stable or not and it was revealed that optimized formulation was found stable for the period of six months. Conclusion: It was revealed that emulgel loaded with high dose of vitamin D-3 and SNPs found suitable to accelerate wound healing and showed almost similar response in wound contraction on comparison with marketed formulation. This emulgel promised to controlled the delivery of the drug for the longer duration.

Physiologically based absorption modeling to predict the bioequivalence of two apixaban formulations.

The equivalence of absorption rates and extents between generic drugs and their reference formulations is crucial for ensuring therapeutic comparability. Bioequivalence (BE) studies are widely utilized and play a pivotal role in substantiating the approval and promotional efforts for generic drugs. Virtual BE simulation is a valuable tool for mitigating risks and guiding clinical BE studies, thereby minimizing redundant invivo BE assessments. Herein, we successfully developed a physiologically based absorption model for virtual BE simulations, which precisely predicts the BE of the apixaban test and reference formulations. The modeling results confirm that the test and reference formulations were bioequivalent under both fasted and fed conditions, consistent with clinical studies. This highlights the efficacy of physiologically based absorption modeling as a powerful tool for formulation screening and can be adopted as a methodological and risk assessment strategy to detect potential clinical BE risks.

Apixaban Pharmacokinetics and Bioequivalence of Two Tablet Formulations: A Randomized, Open-Label, Crossover Study, Fasting Condition in Healthy Indonesian Volunteers.

The present study aimed to assess the bioequivalence of a new apixaban generic with reference formulation. Twenty-six healthy volunteers were recruited for an open-label, balanced, randomized, 2-treatment, 2-sequence, 2-period, single oral dose study. Following overnight fasting, each volunteer received 5mg of apixaban test and reference formulations as single doses, separated by a 1-week washout period. Twenty blood samples were collected at predose and multiple time points between 0.5 and 72 hours after dosing. A validated ultra-performance liquid chromatography-tandem mass spectrometry detection method following a protein precipitation step was implemented to determine apixaban concentrations. Noncompartmental analysis was used to derive the pharmacokinetic parameters, which were then compared between the test and reference products using a multivariate analysis of variance. The pharmacokinetic parameters of the test product were not statistically different from the reference product, and the 90% confidence intervals of apixaban natural log-transformed area under the concentration-time curve from time 0 to infinity, area under the concentration-time curve from time 0 to the last measurable concentration, and maximum concentration were within 80%-125% based on the bioequivalence acceptance range criteria. The test and reference formulations of apixaban are bioequivalent in healthy subjects under fasting conditions.

An In Vitro Study to Evaluate the Antimicrobial Activity of a Zinc Citrate, Sodium Fluoride, Alum and Xylitol-Based Toothpaste Formulation.

Periodontitis is a prevalent condition significantly affecting oral health. Comorbid conditions, such as diabetes, can heighten the severity of periodontal disease and overall oral health. Therefore, to enhance oral health and manage comorbid conditions, comprehensive periodontal care is essential. This approach could involve using toothpaste containing antimicrobial ingredients in routine oral care. This paper presents the results of an in vitro study analysing the antimicrobial properties of the test formulation containing zinc citrate, alum, sodium fluoride, and xylitol-based toothpaste(Stolin-R).These ingredients work together to help in providing comprehensive oral care by controlling growth of bacteria majorly responsible for periodontal disease and thus maintaining optimal oral hygiene. To determine the antimicrobial properties of zinc citrate, alum, sodium fluoride, and xylitol-based toothpaste formulationagainst key periodontal pathogens through in vitro analyses. The antimicrobial efficacy of test formulationis evaluated through minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and time-dependent antibacterial assessment against key periodontal pathogens, including Porphyromonas gingivalis, Tannerella forsythia, Fusobacterium nucleatum, Prevotella intermedia, Streptococcus mutans, and Bacteroides fragilis. The test formulationdemonstrated potent antimicrobial effectiveness against Bacteroides fragilis, Fusobacterium nucleatum, Porphyromonas gingivalis, Prevotella intermedia, Streptococcus mutans, and Tannerella forsythia, by exhibiting low MIC and MBC. Additionally, significant bacterial reduction, exceeding 99.99%, was observed within five minutes, emphasising its potential as an effective adjunct in combating periodontal infection. Zinc citrate, alum, sodium fluoride, and xylitol-based toothpaste formulation demonstrates significant antimicrobial activity against key periodontal pathogens, suggesting its potential as an effective agent for maintaining oral health and combating gingival infection.

Evaluation of Ornidazole Tablets Bioequivalence in Chinese Healthy Participants Under Fasted and Fed Conditions Using Pharmacokinetic Parameters.

Ornidazole, the third generation of nitroimidazole derivatives after metronidazole and tinidazole, it exerts both bactericidal and antiprotozoal effects. The purpose of this study was to evaluate the pharmacokinetic and bioequivalence of two ornidazole tablets manufactured by two different manufacturers based on their pharmacokinetic parameters. Fasted and fed healthy Chinese volunteers participated in a randomized sequence, single-dose, open-label, two-period crossover trial. There were 24 participants in both the fed studyand the fastedstudy. Following a 7-day washout period before receiving the alternative formulation, eligible research participants were randomly assigned (1:1) to receive a single dosage of either the reference formulation or the test formulation. Following tablet administration, plasma samples were obtained over 72 h and analyzed using liquid chromatography tandem mass spectrometry (LC-MS/MS) to evaluate ornidazole contents. maximum plasma concentration (Cmax), time to Cmax (Tmax),the area under the curve (AUC) from t = 0 to infinity (AUC0-∞), AUCfrom t = 0 to the last quantifiable concentration (AUC0-t), half-life (t1/2),and terminal elimination rate constant (z) were evaluated as pharmacokinetic (PK) parameters. The safety evaluation involved adverse events (AEs) incidence and alterations in laboratory tests (hepatic function, blood biochemistry, hematology, and urinalysis) or vital signs (temperature, pulse, and blood pressure). For the bioequivalence assessment in the fast trial, the prime PK parameters comparison between the reference and test formulation revealed that the GMR (90% CI) values for AUC0-t, Cmax, and AUC0-∞ were 100.97% (99.12-102.85%), 99.88% (90.63-110.08%), and 101.12% (99.17-103.11%), respectively. For the bioequivalence assessment in the fed trial, the key PK parameters comparison between the reference and test formulations revealed that the GMR (90% CI) values for AUC0-t, Cmax, and AUC0-∞ were 103.00% (100.94-105.11%), 101.90% (99.63-104.22%), and 102.99% (100.87-105.16%), respectively. The geometric mean ratios (GMRs) for the primary pharmacokinetic parameters (Cmax, AUC0-72, and AUC0-∞) between the two formulations and the corresponding 90% confidence intervals (CIs) were all within the range of 80.00-125.00% for both the fasting and fed states. Both treatments have comparable safety profiles. The bioequivalence and tolerability of ornidazole tablet reference and test formulations were evaluated among healthy Chinese participants under both fasting and fed conditions. The results indicated that both formulations were bioequivalent and generally well tolerated; besides, the interaction between food and drug may affect drug pharmacokinetics. CTR20212873, registered on 15 November 2021; ChiCTR2300069098, registered on 7 March 2023.

Dissolution enhancement of Gefitinib by solid dispersion and complexation with β-cyclodextrins: In vitro testing, cytotoxic activity, and tablet formulation

Cancer is the leading cause of mortality worldwide. In patients with metastatic non-small cell lung cancer, epidermal growth factor receptor (EGFR) is often overexpressed. Gefitinib (GEF), an inhibitor of EGFR, is approved for the treatment of patients with metastatic non-small cell lung cancer (NSCLC). However, the low solubility and dissolution of GEF limits its bioavailability. Numerous methods, including solid dispersion (SD) and complexation, have been reported to enhance the dissolution of poorly soluble drugs. In this study, GEF complexes were prepared using methyl-β-cyclodextrin (MβCD) and hydroxypropyl-β-cyclodextrin (HPβCD) in two molar ratios (1:1 and 1:2), furthermore, GEF SDs were prepared using polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), and poloxamer-188(PXM) in three different ratios (1:2, 1:4 and 1:6 w/w). Dissolution studies were conducted on the prepared formulations. Dissolution results showed a 1.22–2.17-fold enhancement in drug dissolution after one hour compared to untreated GEF. Two formulations that showed higher dissolution enhancement were subsequently evaluated for in-vitro cytotoxicity and were formulated into tablets. The selected PVP–GEF (1:4 w/w) and MβCD–GEF (1:1M) formulas displayed improved cytotoxicity compared to untreated GEF. The IC50 values of the PVP–GEF and MβCD–GEF were 4.33 ± 0.66 and 4.84 ± 0.38 µM, respectively which are significantly lower (p < 0.05) than free GEF. In addition, the formulated tablets exhibited enhanced dissolution compared to pure GEF tablets. PVP–GEF SD tablets released (35.1 %±0.4) of GEF after one hour, while GEF-MβCD tablets released (42.2 % ± 0.7) after one hour. In the meantime, tablets containing pure GEF showed only 15 % ± 0.5 release at the same time. The findings of this study offer valuable insights for optimizing the dissolution and hence therapeutic capabilities of GEF while mitigating its limitations.

Pharmacokinetics and Bioequivalence of Two Combination Metformin/Glipizide Tablets under Fasting and Fed Conditions in Chinese Healthy Subjects: A Randomized, Open-Label, Crossover Study

Metformin/glipizide tablets are a compound formulation composed of metformin hydrochloride and glipizide. This study aimed to assess the pharmacokinetics and bioequivalence of two fixed-dose combination (FDC) tablets of metformin/glipizide (500 mg/2.5 mg) in healthy Chinese subjects. We conducted a single-center, open-label, randomized, two-way crossover study with a total of 48 subjects enrolled (24 in each dietary group). The test or reference formulations were given to the subjects at random at a ratio of 1 : 1, with a seven-day washout period. Blood samples, collected at prearranged intervals before and up to 24 hours after dosage, were analyzed using validated LC-MS/MS technology to ascertain plasma concentrations of metformin and glipizide. Finally, 23 subjects completed the fasting and fed studies, respectively. In both studies, the 90% confidence intervals for the geometric mean ratios (test/reference) of the Cmax, AUC0-t, and AUC0-∞ were all found to fall within the acceptable range for bioequivalence (80%–125%). The exposure of metformin/glipizide FDC tablets in vivo was not significantly affected by food. No serious adverse events were observed. In conclusion, this study demonstrated that both the test and reference metformin/glipizide tablets exhibited bioequivalence and were well tolerated under both fasting and fed conditions. This trial is registered with CTR202686.

A crossover study to evaluate the pharmacokinetics and bioequivalence of hydroxychloroquine tablets in healthy Chinese subjects.

Hydroxychloroquine (HCQ) has a high variability and a long half-life in the human body. The purpose of this study was to evaluate the bioequivalence of a generic HCQ tablet (test preparation) versus a brand HCQ tablet (reference preparation) under fasting and fed conditions in a crossover design. This was an open-label, two-period randomized, single-dose, crossover study in 47 healthy Chinese subjects who were sequentially and randomly allocated either to the fed group (high-fat meal; n = 23) or the fasting group (n = 24). Participants in each group were randomized to the two arms to receive either a single 200-mg dose of the test preparation or a 200-mg dose of the reference preparation. The application of the two preparations in each patient was separated by a 28-day washout period, regarded as sufficiently long to avoid significant interference from residual drug in the body. Whole blood samples were collected over 72 hours after drug administration. A total of 23 subjects completed both the fed and the fasting parts of the trial. There were no significant differences in Cmax, AUC0-72h, and T1/2 between the test and reference preparation (p < 0.05). Food had no significant effect on Cmax and T1/2 (p < 0.05), but AUC0-72h values were significantly reduced under fed condition compared to fasting condition (p < 0.05). The 90% confidence intervals (CIs) for the geometric mean ratios (GMRs) of Cmax and AUC0-72h were 0.84 - 1.05 and 0.89 - 0.98 in the fed study, and 0.97 - 1.07 and 0.97 - 1.05 in the fasting study, respectively. The carryover effect due to non-zero blood concentrations resulted in higher AUC0-72h values in the second period for both test and reference formulations and had no effect on the statistical results. No serious adverse events were reported. The investigation demonstrated that the test and reference preparations are bioequivalent and well tolerated under both fasting and fed conditions in healthy Chinese subjects.

In Vitro Immunomodulatory Activity of Sagalanoi Chooranam (Poly Herbal Formulation) in RAW Macrophage Cell Line

Within the realm of Siddha medicine, an ancient and venerable traditional healing system hailing from India, a comprehensive methodology is deployed to combat liver disorders. This approach is characterised by the utilisation of herbal remedies, accentuating the reinstatement of equilibrium in the body's vital life force, known as "Vatham," "Pitham," and "Kapham." The utilisation of cell line studies is crucial in assessing the immunomodulatory properties of herbal medicine, offering invaluable insights into their capacity to influence the immune system and advancing our comprehension of their therapeutic benefits. The primary objective of this investigation was to elucidate the potential immunomodulatory properties of sagalanoi chooranam, a polyherbal Siddha formulation, through the execution of anti-proliferative assays conducted. On the RAW 264.7 macrophage cell line. Various test solutions were precisely prepared, encompassing a spectrum of concentrations (50, 100 and 200 μg/ml). The RAW 264.7 cells were diligently cultured and then carefully subjected to stimulation with lipopolysaccharide (LPS) to initiate cellular activation. Following this activation, the test formulation was introduced at varying concentrations, after which the cells underwent a 24-hour incubation period. The resultant nitrite levels, serving as indicators of immunomodulatory response, were evaluated within the cell lysate. The outcomes unveiled a notable decline in nitrite levels, correlating with the dosage of the test formulation during the incubation with RAW 264.7 cells. The outcomes of the study elucidate a conspicuous decline in nitrite levels in direct correlation with escalating concentrations of the test formulation, contrasting starkly with the control group exclusively subjected to LPS. Furthermore, the investigation meticulously probed the ramifications of the test formulation on cellular viability. The vitality of RAW 264.7 cells exhibited a discernible downward trajectory as the concentration of the test formulation ascended. Noteworthy is the fact that, at the concentration of 200 μg/ml, cellular viability registered at a mere 55.53 ± 3.567%. Collectively, these findings lend credence to the hypothesis that the test formulation possesses a dose-dependent capacity to attenuate both nitrite levels and cellular viability within the RAW 264.7 cell milieu, underscoring its auspicious immunomodulatory attributes. This research expands our insights into the potential immunological ramifications of the test formulation and underscores its plausible utility within the realm of immunomodulation.

Bioequivalence of Related GelShieldⓇ Sustained-release Formulations of Metformin: A Pooled Pharmacokinetic Analysis

PurposeGlucophageⓇ (Merck Healthcare KGaA, Darmstadt, Germany) is the originator brand of metformin hydrochloride, an oral antidiabetic drug. Metformin is recommended in guidelines as first-line treatment of type 2 diabetes mellitus and increasingly in related insulin-resistant conditions, such as prediabetes and polycystic ovary syndrome. The GelShieldⓇ sustained-release formulation tablet of GlucophageⓇ has been improved from the historic version marketed in 2000. Bioequivalence has been demonstrated stepwise along this evolution; however, a head-to-head evaluation between the initial and the current version is missing. This analysis aims to close this gap and to determine bioequivalence between related originator GelShieldⓇ sustained-release formulations of metformin, GlucophageⓇ (GXR 500 mg), from Europe and the United States. MethodsData from seven randomized crossover bioequivalence studies in 361 healthy participants of Asian and non-Asian ethnicity from Europe, the United States, and Asia were considered. All evaluated a single oral dose of 500 mg of the test and reference formulation in healthy male and female participants in fed and fasted state. Bioequivalence was evaluated by means of a combined bridging analysis of available data on the current round tablet from Europe (rGXR EU) and the historic oblong tablet from the United States (oGXR US) in healthy Asian and non-Asian participants under fed and fasting conditions. Bioequivalence between the two formulations was assessed statistically with a mixed effects model for AUC0-t, Cmax, and AUC0-inf. FindingsIn all studies, bioequivalence between the respective test and reference formulations of GXR was shown. Statistical analysis of pooled pharmacokinetic data of 2 (primary pooling set) or 3 studies (secondary pooling set) demonstrated bioequivalence between rGXR EU and oGXR US via bridging with oGXR EU. The 90% CI for the geometric mean ratio of all pharmacokinetic parameters was within the bioequivalence range of 0.80 to 1.25. In the primary pooling set, geometric least squares mean ratios in the fed group ranged from 0.9931 (90% CI, 0.9151–1.0778) for AUC0-inf to 1.1344 (90% CI, 1.0711–1.2014) for Cmax; results in the fasted group were similar. The secondary pooling set, which added a study in Asians, confirmed these findings. ImplicationsBioequivalence was determined between sustained-release formulations of GlucophageⓇ from Europe and the United States under fasted and fed conditions in healthy men and women, including different ethnicities. The efficacy and safety of GlucophageⓇ XR can be claimed along the evolution from oGXR US, via oGXR EU to rGXR EU, and in several ethnicities and production sites.

Development and Validation of Matrix of Chemistry, Manufacturing, and Control (MoCMC) System for Intramammary Drug Products (IMM).

Products formulated for intramammary (IMM) infusion are intended for the delivery of therapeutic moieties directly into the udder through the teat canal to maximize drug exposure at the targeted clinical site, the mammary gland, with little to no systemic drug exposure. Currently, to our knowledge, there has been no in-vitro matrix system available to differentiate between IMM formulations. Our goal is to develop A custom tailored in-vitro "Matrix of Chemistry, Manufacturing and Control" (MoCMC) System to be a promising future tool for identifying inequivalent IMM formulations. MoCMC can detect inter and intra batch variabilities, thereby identifying potential generics versus brand product similarities or differences with a single numeric value and a specific& distinctive fingerprint. The FDA-approved IMM formulation, SPECTRAMASTⓇ LC, was selected as the reference product for the MoCMC. Twelve in-house test formulations containing ceftiofur hydrochloride were formulated and characterized. The MoCMC was developed to include six input parameters and three output parameters. The MoCMC system was used to evaluate and compare SPECTRAMASTⓇ LC with its in-house formulations. Based on the MoCMC generated parameters, the distinctive fingerprints of MoCMC for each IMM formulations, and the statistical analyses of MCI and PPI values, in-house formulations, F-01 and F-02 showed consistency while the rest of in-house formulations (F-03-F-12) were significantly different as compared to SPECTRAMASTⓇ LC. This research showed that the MoCMC approach can be used as a tool for intra batch variabilities, generics versus brand products comparisons, post-approval formulations changes, manufacturing changes, and formulation variabilities.

Population pharmacokinetic study of imipramine in Taiwan people healthy volunteers

Imipramine is an antidepressant drug (ADs) that shows therapeutic efficacy in a maximum of 60–80% of patients who have experienced a major depressive episode (unipolar or bipolar). The purpose of the study was to investigate the pharmacokinetics of a multi-oral dose of Imipramine 25 mg tablet in a Taiwan healthy population. The study was a standard two-way, crossover, randomized, and single dose daily for 5 days study with a two-week washout period in 30 healthy volunteers who received 25 mg imipramine tablets (test and reference formulation). After drug administration, blood samples were taken according to the planned times over a period of 24 hours. The plasma concentrations of Imipramine were determined using the validated high-performance liquid chromatography method with ultraviolet detection. All the pharmacokinetic parameters for Imipramine in healthy volunteers were calculated using nonlinear mixed-effect modeling and standard non-compartmental methods. Values (relative standard error (RSE) %) for first-order absorption rate constant (Ka), oral clearance (Cl/F), and apparent volume of distribution (Vd/F) were 1.05 (7.11) 1/h, 6.99(0.27) L/h, and 71.7.9(4.80) L. The median for the time to peak plasma Imipramine concentration (Tmax) for the test and reference drug was 2(1.1-4) hours and 4(1.9-5) hours respectively. In conclusion, the imipramine pharmacokinetic model in the Taiwan healthy population was similar to other studied populations.

Pharmacokinetic and pharmacodynamic evaluation study of etomidate: a randomized, open-label, 2-period crossover study in healthy Chinese subjects

Etomidate is a sedative and hypnotic drug through intravenous administration that act on the central nervous system through GABA (Gamma-Amino Butyric Acid) receptors, which is widely used in anesthesia induction and maintenance and long-term sedation in severe patients. The study aimed to evaluate the pharmacokinetic and pharmacodynamic properties of two etomidate fat emulsions after administration through the intravenous infusion pump in healthy Chinese subjects. A randomized, open-label, 2-period crossover study was performed in 52 healthy subjects. The wash-out period was 7 days. Blood samples and pharmacodynamic index values were collected at the specified time points. Etomidate concentrations were measured using validated liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were analyzed using a non-compartment model method. Pharmacodynamic parameters were calculated using pharmacodynamic index values. The study also evaluated the safety of the etomidate. Both the pharmacokinetic parameters and pharmacodynamic parameters result of the test and reference formulation were very similar. The 90% confidence intervals (CI) of the geometric least-squares mean (GLSM) ratios of the test to reference formulation were 91.33–104.96% for the maximum plasma concentration (Cmax), 97.21–102.03% for the area under the plasma concentration time curve from time 0 to the time of the last measurable concentration (AUC0–t), and 97.22–102.33% for the area under the plasma concentration time curve from time 0 to infinity (AUC0–∞). Meanwhile, the 90% CI of the GLSM ratios of the test to reference formulation were 102.28–110.69% for the minimal BIS value (BISmin), 99.23–101.17% for the area under the BIS time curve from time 0–60 min after administration (BISAUC0–60 min), respectively. The 90% CI of these pharmacokinetic and pharmacodynamic parameters all fall in the accepted bioequivalence range of 80.00–125.00%. No serious adverse events occurred during the study. This study has shown that the etomidate fat emulsion test and reference formulation had similar pharmacokinetic and pharmacodynamic characteristics in vivo. The two formulations exhibited good safety and well-tolerance.Clinical trials registration number:http://www.chinadrugtrials.org.cn/index.html. # CTR20191836.

Evaluation of Bioequivalence for Avapritinib Tablets in Chinese Participants Under Fasting Conditions Using a Reference-Scaled Average Bioequivalence Method.

This study aimed to assess the bioequivalence of 2 avapritinib tablets formulations. A randomized, open-label, single-center trial was conducted on fasting, healthy Chinese participants. The study utilized a partial replicated design with 3 sequences and 3 periods. Participants were assigned to 1 of 3 sequences, with each sequence receiving the reference formulation twice and the test formulation once. Plasma samples were collected and analyzed to determine pharmacokinetic parameters. The bioequivalence of the 2 avapritinib formulations was assessed using reference-scaled average bioequivalence for the maximum plasma concentration (Cmax) and the average bioequivalence analysis for the area under the concentration-time curve (AUC). Out of 39 participants, 38 completed the study. For Cmax, the 1-sided 95% upper confidence interval (CI) bound from the scaled approach was -0.035 (<0) and the point estimate value was 0.958, falling inside the acceptance range of 0.8-1.25. For both the AUC over all concentrations measured (AUC0-t) and the AUC from time 0 to infinity (AUC0-inf), the 90% CIs of geometric mean ratios (0.87-1.01) also met the bioequivalence criteria of 0.8-1.25. Consequently, the study demonstrated that the 2 avapritinib formulations were bioequivalent under fasting conditions.

A nanocomposite competent to overcome solubility and permeation issues of capsaicin and thiocolchicoside simultaneously in gout management: Fabrication of nanocubosomes

This study aimed to formulate nano-cubosomes (NCs) co-loaded with capsaicin (CAP) and thiocolchicoside (TCS) to enhance their bioavailability and minimize associated potential side effects through transdermal delivery alongside their synergistic activity. Twenty seven (27) nano-cubosomal dispersions were prepared according to Box-Behnken factorial design and the effect of CAP, TCS, glyceryl mono oleate (GMO) and poloxamer 407 (P407) concentrations on particle size, polydispersity index (PDI), zeta potential, and entrapment efficiency were assessed. The results revealed that the optimized formulation exhibited a mean droplet size of 503 ± 10.3 nm, PDI of 0.405 ± 0.02, zeta potential of −10.0 ± 1.70 mV and entrapment efficiency of 86.9 ± 3.56 %. The in vivo anti-inflammatory effect of optimized formulation was studied in rats by injecting carrageenan to induce edema. The results of in vivo study showed that transdermal application of nano-cubosomes co-loaded with CAP and TCS significantly (p value < 0.05) improved carrageenan induced inflammation compared with standard treatment. The analgesic activity of optimized formulation was evaluated in rats by using Eddy’s hot plate method. The findings of analgesic activity illustrated that the analgesic effects exhibited by test formulation may be associated with increased licking period and inhibition of prostaglandins level. In conclusion, the transdermal application of NCs co-loaded with CAP and TCS may be a promising delivery system for enhancing their bioavailability as well as synergistic analgesic and anti-inflammatory activity in gout management.

Dissolution Profiles of Oral Disintegrating Tablet with Taste Masking Granule Polymer Coating in Biorelevant Bicarbonate Buffer.

The current study aimed to explore the impact of buffer species on the dissolution behavior of orally disintegrating tablets (ODT) containing a basic polymer and its influence on bioequivalence (BE) prediction. Fexofenadine hydrochloride ODT formulations were used as the model formulations, Allegra® as the reference formulation, and generic formulations A and B as the test formulations. Allegra®, generic A, and generic B are ODT formulations that contain aminoalkyl methacrylate copolymers E (Eudragit® E, EUD-E), a basic polymer commonly used to mask the bitter taste of drugs. Both generic A and generic B have been known to be bioequivalent to Allegra®. The dissolution tests were conducted using a compendial paddle, with either bicarbonate (10 mM, pH 6.8) or phosphate buffer (25 mM, pH 6.8) as the dissolution media. A floating lid was employed to cover the surface of the bicarbonate buffer to prevent volatilization. Results indicated that in phosphate buffer, the dissolution profiles of Allegra and generic B significantly varied from that of generic A, whereas in the bicarbonate buffer, the dissolution profiles of Allegra, generic A, and generic B were comparable. These findings suggest that the use of bicarbonate buffer may offer a more precise prediction of human bioequivalence compared to phosphate buffer.

Exploring the validity and reliability of Active Motor Card: A Comprehensive Assessment of Gross Motor Development and Physical Fitness in Children Aged 6-9 Years

This research presents the Active Motor Card, an innovative evaluation instrument meticulously designed to comprehensively assess gross motor skills and physical fitness development in children aged 6-9 years. The study identifies the essential elements of motor development and physical fitness, highlighting the need for tailored assessments within this age group. The research delineates the process of development, encompassing an extensive review of existing literature, formulation of hypothetical tests, evaluation of content validity, empirical validation, and reliability assessment. The resultant Active Motor Card is validated by experts, thereby demonstrating its alignment with the target population's characteristics. Furthermore, the Gregory Analysis corroborates the appropriateness of each test item, indicating their level of difficulty or ease and their conformity with the expected characteristics of children aged 6-9. The reliability test, utilizing the Cronbach's alpha coefficient, affirms the consistency of the assessment. This product, designed for utilization in various settings, holds great potential as an effective instrument for monitoring children's motor skills and physical fitness, thereby making a positive contribution to the domains of physical education and sports. Further research is advisable to explore additional dimensions and enhance the assessment's validity, complexity, and representativeness across diverse populations. Keywords: Active Motor Card, gross motor development, physical fitness, children aged 6-9 years.

Pharmacokinetics and bioequivalence of tofacitinib 5 mg in healthy Korean male subjects.

Tofacitinib is an oral Janus kinase (JAK) inhibitor marketed as an immunomodulator that can effectively treat rheumatoid arthritis. This study aimed to compare the pharmacokinetics and evaluate the bioequivalence of tofacitinib free base (CKD-374) with those of tofacitinib citrate (Xeljanz). A randomized, open-label, single-dose, 2-sequence, 2-period crossover study was conducted in healthy Korean male subjects. A total of 36 subjects were randomized into two sequence groups. At each period, subjects were administered the test formulation (tofacitinib free base, 5 mg) or the reference formulation (tofacitinib citrate, 8.078 mg; as tofacitinib, 5 mg). The plasma samples were collected up to 12 hours post dose and analyzed by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters, including maximum plasma concentration (Cmax) and area under the plasma concentration vs. time curve from dosing to the last measurable concentration (AUC0-t), were determined by non-compartmental analysis. The 90% confidence intervals (CIs) of the geometric mean ratios for Cmax and AUC0-t were calculated to evaluate pharmacokinetic equivalence. The 90% CIs of the geometric mean ratios of Cmax and AUC0-t for tofacitinib free base to tofacitinib citrate were 0.9144-1.1230 and 1.0245-1.0932, respectively. All reported adverse events were of mild intensity, and there were no serious adverse events. In healthy Korean male adult subjects, the pharmacokinetic parameters of tofacitinib free base and tofacitinib citrate were evaluated and met the pharmacokinetic bioequivalent criteria. Both formulations were safe and well-tolerated.