Test Formulation Research Articles

Development of dexibuprofen loaded nano transfersomal gel with enhanced biopharmaceutical performance in complete Freund's adjuvant induced arthritis model

The purpose of this study was to enhance the biopharmaceutical performance of Dexibuprofen (DXI) using transfersomal gel (DXI-TG) as drug delivery system. DXI loaded transfersomes (DXI-T) were prepared via thin film technique, characterized for particle size, polydispersity index, zeta potential, particle morphology and entrapment efficiency. The DXI-T was further incorporated into 2 % (w/v) chitosan gel to get the final dosage form DXI-TG, which was characterized for homogeneity, pH, spread-ability and rheological properties. In vitro release, ex vivo permeation and in vivo studies were also conducted along with stability study of the optimized formulation. DXI-T showed excellent vesicle properties including, size distribution (235.1 ± 4.66 nm), poly dispersity index (0.184 ± 0.001), zeta potential (−10.5 ± 0.23 mV) and entrapment efficiency (82.9 ± 1.07 %). TEM analysis exhibited spherical morphology and uniformly distributed nanoparticles, whereas FTIR showed no bond anomalies. DXI-TG showed suitable gel properties with a viscosity of 11310 ± 20 cP, pH 5.2 ± 0.3, good homogeneity, non-Newtonian flow behavior, good spread-ability (298 ± 7.63 %) and high drug content (97.01 ± 3.1 %). in vitro release studies demonstrated that DXI-TG has significantly controlled the release of DXI when compared with DXI-T, DXI-G and DXI-Suspension at pH 5.5 and 7.4. Similarly, ex vivo permeation analysis showed meaningfully increased permeation of DXI-T followed by DXI-TG when compared with test formulations. Like normal control group, skin irritation studies showed no erythema and edema in DXI-TG treated group. Additionally, DXI-TG demonstrated a significantly enhanced bioavailability (5-fold) when compared with DXI-Suspension and DXI-G. Furthermore, DXI-TG showed significantly enhanced therapeutic effect against acute arthritis model when compared with DXI-Suspension and DXI-G. Besides, no signs of evident toxicity on major body organs was observed in DXI-TG treated animal group. Also, the DXI-TG was found stable for a period of 6 months. It can be concluded that transfersomal gel may be a suitable carrier for DXI with enhanced bioavailability, improved therapeutic efficacy and no evident toxicity as exhibited in this study.

An exploratory study of a multi-species probiotic formulation and markers of health in a real-world oncological cohort in the time of covid

IntroductionThe efficacy of cancer treatments has links to the intestinal microbiome. Mucositis is a dose-limiting intestinal pro-inflammatory side effect of cancer treatments, that increases the risk of diarrhoea, mucositis, and in severe cases, febrile neutropenia.MethodsThe effect of cancer treatments on Quality of Life (QoL) was assessed using the FACT C questionnaire that included patient wellbeing and gut adverse symptoms (e.g. diarrhoea). Participants rated faecal samples via the Bristol Stool Chart. In addition, bacterial DNA was extracted from faecal samples, sequenced, and taxonomically examined. The incidence / severity of neutropenia was assessed with white blood cell and neutrophil counts. Circulating SCFAs and plasma lipopolysaccharide (LPS) endotoxin levels were recorded and correlated to intestinal mucositis.ResultsImprovement in bowel function, with reduction in constipation and or diarrhoea or absence of significant disturbance to bowel function was recorded in 85% of the participants. One participant developed febrile neutropenia and two developed bowel toxicity during the study, that was unrelated to the test formulation. No significant changes in microbiota alpha- and beta-diversity at the phylum and species levels respectively from baseline to end of study treatment was observed. None of the participants had raised plasma-endotoxin levels from baseline to the first and subsequent treatment cycles for their cancers. Probiotics in this cohort were deemed safe and tolerable. Significant improvement in emotional QoL scores (p = 0.015) was reported with increased number of chemotherapy cycles. In a related observational study of exceptional responders to chemotherapy, participants were found to have had a high intake of fruits, vegetables, and fibre possibly indicative of a more balanced intestinal microbiota.ConclusionA multi-strain probiotic formulation was safe and tolerated in this chronically ill cohort that were undergoing oncological treatment. The probiotic formulation alleviated diarrhoea, constipation and maintained stool consistency/frequency during the multiple treatments with chemotherapy and radiotherapy. Intestinal dysbiosis that is characterised by decreased microbial diversity and increased pro-inflammatory species was not observed. Probiotic supplementation may have helped reduce dysbiosis during cancer treatments. These improvements may have been critical with the observation that emotional wellbeing was significantly improved from baseline. Hence albeit that the study had limitations, the probiotic intervention provided adjunctive treatment support to the patients. What is of scientifically plausible interest is that probiotics have a long association historically with human hosts and as such ratify their inclusion offering a significant adjunctive therapeutic potential. Future studies warrant larger sample sizes, control groups and should limit recruitment to a largely homogenous group of patients.

Antioxidant, Anti-inflammatory and Anthelminthic Activities of Traditionally used Ocimum basilicum L., and Ocimum tenuiflorum L. Extract Loaded Emulsion

The demand for cosmeceuticals is rapidly expanding. Various phytoconstituents are identified from Ocimum basilicum and O. tenuiflorum and have several pharmacological properties. The present study aimed to formulate a novel alternative herbal formulation for topical administration with natural antioxidant properties for the treatment of inflammatory conditions with the destructive capacity of parasitic worms. The egg albumin denaturation technique was used to evaluate the test formulations’ and the standard’s in-vitro anti-inflammatory properties, and the hydrogen peroxide assay was used to measure the extracts’ antioxidant properties. Eudrilus eugeniae was the target of the investigation into in-vitro anthelmintic action. The pH of the cream was 6.8 (average), it was easily spreadable and washable, no gritty particles were found and the dye test confirmed that it was an o/w type of cream. The egg albumin denaturation technique was utilized to evaluate the anti-inflammatory properties. The results cleared those herbal formulations (F1 and F2) and protein denaturation was decreased by diclofenac sodium (Standard) in a dose-dependent manner. Test samples exhibited higher anti-inflammatory activities than the standard with their percentage inhibitions being 41.5 ± 0.5 (F2), 39.1 ± 0.4 mg/mL (F1), and 37.3 ± 0.3 mg/mL (F-Standard), respectively. Antioxidants are compounds that either completely stop or significantly reduce the harm that free unstable radicals. F2 showed a higher concentration-dependent anthelmintic activity than F1 and standard albendazole. Increasing the concentration decreases the paralysis and death time of earthworms. Finally concluded that F2 indicates higher anti-inflammatory and anthelmintic activities than others with high natural antioxidant power.

A proof of principle investigation of a novel enzyme formulation on dental calculus deposition: a 4-week randomized human clinical trial

BackgroundThe dissolution of dental calculus, safely and at home, is among the more challenging issues facing the over-the-counter healthcare industry. Pontis Biologics, Inc. has developed novel model of calculus development and structure and has formulated a dentifrice (Tartarase™) using digestive enzymes as active ingredients that is shown to dissolve dental calculus in this Proof of Principle clinical trial.MethodsThis investigation was designed to evaluate the safety and efficacy of a novel enzyme formulation to remove existing calculus deposits in 4 weeks, measured using the Volpe-Manhold Index (V-MI) on lingual surfaces of 6 lower anterior teeth. The test formulation was compared to Crest Cavity Protection, as a control dentifrice. A total of 40 randomized test subjects began the study with 20 assigned to the control dentifrice and 20 assigned to the Tartarase groups (ten each, one brushing with Tartarase twice daily and one brushed with Tartarase and wore a dental tray filled with Tartarase for 30 min then brushed again with Tartarase, once daily).ResultsThe Crest group experienced a 12% increase in calculus, in contrast to the results of both Tartarase groups that experienced a 40% reduction in calculus in 4 weeks of unsupervised at home use of the Tartarase toothpaste formulation.ConclusionsThis proof of principle study demonstrates that a dentifrice, formulated along the lines of the Tartarase material, is capable of combating calculus accumulation using the same oral hygiene habits that are common worldwide.Trial registrationThis trial was registered retrospectively at clinicaltrials.gov and has the Unique Identification Number: NCT06139835, 14/11/2023.

Model-Based Bioequivalence Analysis to Assess and Predict the Relative Bioavailability of Valproic Acid Formulations.

Model-based bioequivalence (MBBE) encompasses the use of nonlinear mixed effect models supporting the estimation of pharmacokinetic endpoints to assess the relative bioavailability between multi-source drug products. This application emerges as a valuable alternative to the standard non-compartmental analysis (NCA) in bioequivalence (BE) studies in which dense sampling is not possible. In this work, we aimed to assess the application of MBBE compared to traditional methods in evaluating the relative bioavailability of two formulations with different drug release properties. Additionally, we sought to predict the performance of a modified-release formulation in a multiple-dose scenario, leveraging data from a single-dose study. MBBE analysis was implemented to estimate the BE endpoints (90%CI for the Test/Reference geometric mean ratio, T/R GMR) in area under the concentration-time curve (AUC) and maximum concentration (Cmax) using data from a single-dose, 2-period, 2-sequence BE study performed in 14 healthy subjects between a locally developed valproic acid extended-release formulation (Test) and the brand-name delayed-release formulation (Reference). Results were compared with the standard approach, revealing that MBBE analysis achieved higher discrimination between formulations for Cmax, addressing limitations of the experimental sampling design and highlighting an advantage for this model-based analysis even when rich data are available. Additionally, the bioequivalence outcome under the multiple-dose scenario was predicted through a simulation-based study for both total and unbound valproic acid concentrations, considering the impact of valproic acid saturable binding on BE conclusions. The MBBE analysis was superior to the NCA approach in detecting product-related differences, overcoming limitations in the study experimental design. Predictions for the multiple-dose scenario preclude that the extended-release properties of the Test formulation would persist at steady state, resulting in lower peak-to-trough fluctuation and bioequivalent performance in terms of the extent of drug absorption. Overall, these results should discourage unnecessary experimentation in healthy subjects.

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.

The effects of chitosan biofilm in combination with vinegar, sodium alginate, and carboxymethyl cellulose on the transformation of biochemical and physiological indexes of pears during storage

Pears have a characteristically delicious taste and are rich in nutritional value, especially sugar, vitamin C, vitamin A, and minerals. This study aimed to determine the amount of chitosan-derived probiotics that can be combined with edible vinegar and sodium alginate carboxymethyl cellulose to create a pear preservation process. Formulated chitosan in combination with table vinegar, sodium alginate, and carboxymethyl cellulose at a rate of 160 g chitosan/160 mL table vinegar/7,000 mL water, 4 g sodium alginate, and 0.5 g carboxymethyl cellulose to preserve 180 kg of pears. In 5 preservation test formulations, it was determined that the content of probiotics at 1.0% is suitable for preserving pears. When stored in the content of this probiotic, it has limited the transformation of biochemical and physicochemical indexes. Especially by the fourth week of storage, pears still retained their characteristic values; the natural loss rate was only 5.23% and the rot rate was 5.07%, both lower than when stored in other biological products. In comparison to fresh pears before being put into storage, the change in biochemical and physicochemical indexes of preserved pears with a biological content of 1.0% is only a little.

Bioequivalence of a new coated 15 mg primaquine formulation for malaria elimination

BackgroundWith only one 15 mg primaquine tablet registered by a stringent regulatory authority and marketed, more quality-assured primaquine is needed to meet the demands of malaria elimination.MethodsA classic, two sequence, crossover study, with a 10-day wash out period, of 15 mg of IPCA-produced test primaquine tablets and 15 mg of Sanofi reference primaquine tablets was conducted. Healthy volunteers, aged 18–45 years, without glucose-6-phosphate dehydrogenase deficiency, a baseline haemoglobin ≥ 11 g/dL, creatinine clearance ≥ 70 mL/min/1.73 ms, and body mass index of 18.5–30 kg/m2 were randomized to either test or reference primaquine, administered on an empty stomach with 240 mL of water. Plasma primaquine and carboxyprimaquine concentrations were measured at baseline, then 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.333, 2.667, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 10.0, 12.0, 16.0, 24.0, 36.0, 48.0 and 72.0 h by liquid chromatography coupled to tandem mass spectrometry. Primaquine pharmacokinetic profiles were evaluated by non-compartmental analysis and bioequivalence concluded if the 90% confidence intervals (CI) of geometric mean (GM) ratios of test vs. reference formulation for the peak concentrations (Cmax) and area under the drug concentration–time (AUC0–t) were within 80.00 to 125.00%.Results47 of 50 volunteers, median age 33 years, completed both dosing rounds and were included in the bioequivalence analysis. For primaquine, GM Cmax values for test and reference formulations were 62.12 vs. 59.63 ng/mL, resulting in a GM ratio (90% CI) of 104.17% (96.92–111.96%); the corresponding GM AUC0–t values were 596.56 vs. 564.09 ngxh/mL, for a GM ratio of 105.76% (99.76–112.08%). Intra-subject coefficient of variation was 20.99% for Cmax and 16.83% for AUC0–t. Median clearances and volumes of distribution were similar between the test and reference products: 24.6 vs. 25.2 L/h, 189.4 vs. 191.0 L, whilst the median half-lives were the same, 5.2 h.ConclusionIPCA primaquine was bioequivalent to the Sanofi primaquine. This opens the door to prequalification, registration in malaria endemic countries, and programmatic use for malaria elimination.Trial registration The trial registration reference is ISRCTN 54640699

QbD-Based Development and Evaluation of Pazopanib Hydrochloride Extrudates Prepared by Hot-Melt Extrusion Technique: In Vitro and In Vivo Evaluation.

Pazopanib hydrochloride (PZB) is a protein kinase inhibitor approved by the United States Food and Drug Administration and European agencies for the treatment of renal cell carcinoma and other renal malignancies. However, it exhibits poor aqueous solubility and inconsistent oral drug absorption. In this regard, the current research work entails the development and evaluation of the extrudates of pazopanib hydrochloride by the hot-melt extrusion (HME) technique for solubility enhancement and augmenting oral bioavailability. Solid dispersion of the drug was prepared using polymers such as Kollidon VA64, hydroxypropylmethylcellulose (HPMC), Eudragit EPO, and Affinisol 15LV in a 1:2 ratio by the HME process through a lab-scale 18 mm extruder. Systematic optimization of the formulation variables was carried out with the help of custom screening design (JMP Software by SAS, Version 14.0) to study the impact of polymer type and plasticizer level on the quality of extrudate processability by measuring the torque value, appearance, and disintegration time as the responses. The polymer blends containing Kollidon VA64 and Affinisol 15LV resulted in respective clear transparent extrudates, while Eudragit EPO and HPMC extrudates were found to be opaque white and brownish, respectively. Furthermore, evaluation of the impact of process parameters such as screw rpm and barrel temperature was measured using a definitive screening design on the extrude appearance, torque, disintegration time, and dissolution profile. Based on the statistical outcomes, it can be concluded that barrel temperature has a significant impact on torque, disintegration time, and dissolution at 30 min, while screw speed has an insignificant impact on the response variables. Affinisol extrudates showed less moisture uptake and faster dissolution in comparison to Kollidon VA64 extrudates. Affinisol extrudates were evaluated for polymorphic stability up to a 3-month accelerated condition and found no recrystallization. PZB-Extrudates using the Affinisol polymer (Test formulation A) revealed significantly higher bioavailability (AUC) in comparison to the free Pazopanib drug and marketed formulation.

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.

Pharmacokinetic Bioequivalence and Safety Assessment of Two Venlafaxine Hydrochloride Extended-Release Capsules in Healthy Chinese Subjects Under Fed Conditions: A Randomized, Open-Label, Single-Dose, Crossover Study.

Venlafaxine hydrochloride extended-release (ER) capsules are commonly used to treat depression and anxiety disorders. Evaluation of the bioequivalence of generic formulations with reference products is essential to ensure therapeutic equivalence. The objective of this study was to evaluate the bioequivalence, safety, and tolerability of Chinese-manufactured venlafaxine hydrochloride extended-release capsules compared with USA-manufactured EFFEXOR® XR in healthy Chinese volunteers under fed conditions. A randomized, open-label, single-dose, crossover study was conducted. Subjects were randomly assigned to receive the test formulation (one 150-mg ER capsule manufactured in China) or the reference formulation (one 150-mg ER capsule manufactured in the USA). The bioequivalence of the two drugs was assessed using the area under the plasma concentration-time curve from time zero to the last sampling time (AUC0-t) and the maximum observed concentration (Cmax). A total of 28 subjects were enrolled and randomly assigned to receive a single dose of either the test or reference capsule. All the subjects completed the study and were included in the pharmacokinetic (PK) and safety analyses. The mean AUC0-t and Cmax of venlafaxine and its active metabolite O-desmethylvenlafaxine were comparable between the test and reference products with both parameters close to 100% and the corresponding 90% confidence intervals within the specified 80-125% bioequivalence boundary. Safety was also assessed between the two products and all adverse events (AEs) in this study were mild in severity. Both the test and reference venlafaxine hydrochloride ER capsules were bioequivalent and showed a similar safety and tolerability profile in the population studied. This study was registered at the Drug Clinical Trial Registration and Information Publicity Platform ( http://www.chinadrugtrials.org.cn/index.html ) with registration number CTR20211243, date: June 1, 2021.

A Semi-Mechanistic Population Pharmacokinetic Model of Noscapine in Healthy Subjects Considering Hepatic First-Pass Extraction and CYP2C9 Genotypes.

Noscapine is a commonly used cough suppressant, with ongoing research on its anti-inflammatory and anti-tumor properties. The drug has a pronounced pharmacokinetic variability. This evaluation aims to describe the pharmacokinetics of noscapine using a semi-mechanistic population pharmacokinetic model and to identify covariates that could explain inter-individual pharmacokinetic variability. Forty-eight healthy volunteers (30 men and 18 women, mean age 33 years) were enrolled in a randomized, two-period, two-stage, crossover bioequivalence study of noscapine in two different liquid formulations. Noscapine plasma concentrations following oral administration of noscapine 50 mg were evaluated by a non-compartmental analysis and by a population pharmacokinetic model separately. Compared to the reference formulation, the test formulation exhibited ratios (with 94.12% confidence intervals) of 0.784 (0.662-0.929) and 0.827 (0.762-0.925) for peak plasma concentrations and area under the plasma concentration-time curve, respectively. Significant differences in p values (<0.01) were both observed when comparing peak plasma concentrations and area under the plasma concentration-time curve between CYP2C9 genotype-predicted phenotypes. A three-compartmental model with zero-order absorption and first-order elimination process best described the plasma data. The introduction of a liver compartment was able to describe the profound first-pass effect of noscapine. Total body weight and the CYP2C9 genotype-predicted phenotype were both identified as significant covariates on apparent clearance, which was estimated as 958 ± 548 L/h for extensive metabolizers (CYP2C9*1/*1 and *1/*9), 531 ± 304 L/h for intermediate metabolizers with an activity score of 1.5 (CYP2C9*1/*2), and 343 ± 197 L/h for poor metabolizers and intermediate metabolizers with an activity score of 1.0 (CYP2C9*1/*3, *2/*3, and*3/*3). The current work is expected to facilitate the future pharmacokinetic/pharmacodynamic development of noscapine. This study was registered prior to starting at "Deutsches Register Klinischer Studien" under registration no. DRKS00017760.

Silversol® (a Colloidal Nanosilver Formulation) Inhibits Growth of Antibiotic-Resistant Staphylococcus aureus by Disrupting Its Physiology in Multiple Ways.

Antibiotic-resistant strains of Staphylococcus aureus are being viewed as a serious threat by various public health agencies. Identifying novel targets in this important pathogen is crucial to the development of new effective antibacterial formulations. We investigated the antibacterial effect of a colloidal nanosilver formulation, Silversol®, against an antibiotic-resistant strain of S. aureus using appropriate in vitro assays. Moreover, we deciphered the molecular mechanisms underlying this formulation's anti-S. aureus activity using whole transcriptome analysis. Lower concentrations of the test formulation exerted a bacteriostatic effect against this pathogen, and higher concentrations exerted a bactericidal effect. Silversol® at sub-lethal concentration was found to disturb multiple physiological traits of S. aureus such as growth, antibiotic susceptibility, membrane permeability, efflux, protein synthesis and export, biofilm and exopolysaccharide production, etc. Transcriptome data revealed that the genes coding for transcriptional regulators, efflux machinery, transferases, β-lactam resistance, oxidoreductases, metal homeostasis, virulence factors, and arginine biosynthesis are expressed differently under the influence of the test formulation. Genes (argG and argH) involved in arginine biosynthesis emerged among the major targets of Silversol®'s antibacterial activity against S. aureus.

Bioequivalence and Safety of Two Formulations of Tofacitinib Citrate Tablets in Healthy Chinese Volunteers under Fasting and Fed Conditions: Randomized, Open-Label, 2-Period, Single-Dose, Crossover Trials

Purpose. To evaluate the bioequivalence of two different tofacitinib citrate tablets formulations among healthy Chinese subjects under fasting and fed conditions and to observe the safety of test preparation and reference preparation in healthy subjects. Method. This randomized, open-label, 2-period, crossover, bioequivalence study included 64 healthy Chinese subjects (fasting: n = 32, fed: n = 32). The subjects were assigned to receive a single 5-mg dose of the test or a reference tofacitinib citrate tablets. Blood samples were collected at predose and up to 24 hours after dosing. Area under the plasma concentration time curve from zero to the last measurable concentration (AUC0-t), the area from time zero to infinite (AUC0-∞), and maximum plasma concentration (Cmax) were used for bioequivalence assessment. Safety assessment was conducted by vital signs, physical examination, laboratory examination, and 12-lead electrocardiogram during the study, from the time the subject receiving the test drug to the end of the last visit. Results. Under fed condition, the 90% CIs of the geometric mean ratios of the test/reference for tofacitinib citrate tablets were 98.40–104.16% for AUC0-t, 89.96–116.70% for Cmax, and 98.50–104.15% for AUC0-∞. Under fasting condition, the 90% CIs of the geometric mean ratios of the test/reference for tofacitinib citrate tablets were 93.65–101.60% for AUC0-t, 90.06–109.15% for Cmax, and 93.88–101.51% for AUC0-∞. There were no serious events. Conclusion. The 90% CI for the geometric mean ratio (test/reference) of Cmax, AUC0-t, and AUC0-∞ were within the range of 80.00%–125.00%, indicating that the test formulation was equivalent to the reference formulation in healthy Chinese subjects under both fasting and fed conditions. They are similar in terms of safety. This trial is registered with CTR20190366.

RPL Management Model for Capacity Building of Village Apparatus: A Case Study on Cooperation between Surabaya State University and Bojonegoro District Government

Law Number 23 of 2014 grants regional autonomy, which means that each regional institution is authorized to manage its own policies. This includes village governments, which are regulated by Law Number 6 of 2014. Therefore, it is crucial to have competent village personnel who can provide exceptional services to the citizens. In 2021, 45,387 village heads, 43,876 village secretaries, 31,147 village-owned enterprise managers, and 7,889 professional assistants graduated from high school, according to data from the Ministry of Village, Development of Disadvantaged Regions, and Transmigration. This highlights the need to strengthen the education of village apparatus. One way to achieve this is through the Recognition of Prior Learning (RPL) program, which is a collaboration between the Ministry and universities such as the State University of Surabaya and the State University of Yogyakarta. This program can help improve the skills of village apparatus. However, there is a gap between the reality and the implementation of the collaboration between the Ministry and Pertindes regarding the implementation of RPL for village apparatus. In Bojonegoro Regency, for instance, only 61% of village heads had a high school educational background in 2022, according to the Office of Community Empowerment and Village Government. To address this issue, the researcher aims to understand the management of RPL in Bojonegoro Regency to improve the capacity of village apparatus. The research is based at the State University of Surabaya and Bojonegoro Regency. The study obtained primary data from interviews, literature studies, and a memorandum of understanding between the State University of Surabaya (UNESA) and the Bojonegoro Regency Government. The researcher used a knowledge management approach in program planning, which focused on six main stages in development planning. These stages included problem identification, problem diagnosis, design stage, design implementation, design testing, and solution formulation. The results of the study showed that collaboration and support from educational institutions are strategic solutions for improving village human resources. Additionally, the RPL program is relevant to the functions of higher education institutions in preparing personnel for village government administration. The implementation of RPL in Bojonegoro is in accordance with the principles of cooperation. However, there were some technical obstacles in the implementation of activities.

Pharmacokinetics and Bioequivalence of Fixed-Dose Combination of Simvastatin and Ezetimibe Tablets: A Randomized, Crossover, Open-Label Study in Healthy Volunteers.

The current study aimed to evaluate the bioequivalence of a new generic combination of simvastatin and ezetimibe with the reference formulation. An open-label, randomized, 3-period, 3-sequence, crossover study, including 60 healthy volunteers, was implemented. Participants received the test and reference formulation, each containing 20mg of simvastatin and 10mg of ezetimibe as a single-dose tablet, separated by a minimum of 2-week washout periods. Blood samples were collected for 20 time points from predose to 72 hours after the dose. The total ezetimibe assay was carried out using a validated liquid chromatography-tandem mass spectrometry, while unconjugated ezetimibe, simvastatin, and simvastatin β-hydroxy acid determination was done via a validated ultra-performance liquid chromatography-tandem mass spectrometry. Each assay was preceded by a liquid-liquid extraction step. The pharmacokinetic parameters were derived using noncompartmental analysis and then compared between the reference and test formulations via a multivariate analysis of variance. No statistical difference was found in under the concentration-time curve from time 0 to the last quantifiable concentration and maximum concentration of unconjugated ezetimibe, total ezetimibe, and simvastatin between the reference and test formulations. The 90% confidence intervals of unconjugated ezetimibe, total ezetimibe, and simvastatin natural log-transformed under the concentration-time curve from time 0 to the last quantifiable concentration, and maximum concentration were in the range of 80%-125% as per the bioequivalence acceptance criteria. Therefore, the test formulation was bioequivalent to the reference formulation.

The Effect of Employee Performance on Telecommunication Industry in Bangladesh

The study delves into the intricate relationship between employee training and performance outcomes within the telecommunications sector, particularly focusing on Bangladesh. It underscores the crucial role of employee training in driving innovation, maintaining competitiveness, and enhancing organizational performance in an ever-evolving industry landscape. The study defines training effectiveness as the extent to which training programs contribute to improving employee performance across various dimensions such as technical skills, customer service, sales, compliance, and innovation. Using a mixed-methods approach, including survey data and qualitative insights from industry professionals, the study aims to uncover the mechanisms through which training impacts employee performance. It emphasizes the need for robust analysis methods beyond traditional statistical tests like the F-test to capture the complexity of these relationships. Firstly, it provides an overview of the research background, significance, and methodology, setting the stage for subsequent chapters. It identifies the research problem, formulates research questions, and outlines the study's structure, emphasizing the importance of a comprehensive literature review to inform theoretical perspectives and hypothesis formulation. Moreover, the study explores the theoretical basis underlying employee training and performance, defining core concepts such as training effectiveness, performance, satisfaction, and contribution. It discusses theories like Training Value Management Theory, Innovation Theories of Training, and Core Competitiveness Theories of Training, which inform the understanding of how training influences organizational outcomes. Then, it delves into the mechanisms and hypotheses formulation for empirical testing. The research methodology, including sample selection, data collection, and model construction, is discussed, ensuring methodological rigor and ethical considerations. It also presents the data analysis and findings, incorporating both quantitative regression analysis and qualitative insights from interviews. It discusses the effectiveness of training initiatives, challenges faced, and implications for practice, along with limitations and future research directions. Lastly, it offers a comprehensive discussion of the findings, highlighting theoretical and practical implications for organizations in the telecommunications sector. It emphasizes the role of management in optimizing training programs and fostering a culture of continuous learning. Overall, the study sheds light on the critical role of training in shaping employee performance and organizational success in the telecommunications industry of Bangladesh. It offers valuable insights for practitioners, policymakers, and scholars, contributing to the understanding of training effectiveness and its implications in a rapidly evolving digital age.

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.