ArchiveThe research and construction of drug regulatory science has become the focus of drug supervision strategies in the world in this century, and the construction of talent teams is one of the first considerations in the research and construction of regulatory science. China is still in its infancy in the cultivation of regulatory science talents, and there are prominent problems such as the small scale, shallow degree, and chaotic system of talent cultivation. The United States has been exploring the cultivation of talents for drug regulatory science for many years, and has formed a mature regulatory science talent training system. This article studies the innovative practice of the training of regulatory science talents in the United States, analyzes and summarizes its talent training orientation and specific training measures to understand the deficiencies in China, and on the basis of which, suggestions were put forward to improve the cultivation system of drug regulatory science talents in China.
Research on container closure integrity (CCI) is an important part of drug development. This article focuses on the CCI research of the life cycle of the rubber stopper/glass container, including packaging design, production, and stability research, and discusses the MALL establishment of rubber stopper/glass container.
To evaluate the bioequivalence of reference and test formulations of glucosamine sulfate capsules after single dose in healthy Chinese volunteers under fasting condition.
A total of 30 healthy human volunteers participated in a randomized, open, single-dose, three-cycle, partial repeated, three-crossover study. Volunteers were given single dose (0.25 g) of tested and reference formulations of glucosamine sulfate capsules under fasting state. Plasma concentration of glucosamine after administration was analyzed by LC-MS/MS method. Non-compartmental pharmacokinetics parameters were calculated by WinNonlin 6.3, and bioequivalence was evaluated using reference-scaled average bioequivalence (RSABE) method by SAS 7.1.
For test and reference formulations, Cmax of glucamine (after baseline correction) were (585.0±282.2) and (641.0±293.6) ng·mL-1, Tmax were 1.5 (0.5, 5.0) and 1.5 (0.5, 5.0) h, t1/2 were (1.8±1.4) and (1.5±0.5) h, AUC0~t were (2 089.2±749.5) and (2 298.2±928.4), AUC0~∞ were (2 095.3±749.7) and (2 303.1±929.0), respectively. The geometric mean ratios (GMR) of AUC0~t, AUC0~∞ and Cmax between test and reference formulations were both within 90% confidence interval broadened bioequivalent rage 74.9% to 133.6% and 70.1% to 142.7%, and regular bioequivalent range (80% to 125%).
Two formulations were equivalent under fasting condition.
At the beginning of the 21st century, a large number of synthetic cathinones flowed into the illegal market, which are sold as “bath salts” and “plant food” online, and usually labeled “not for human use”. There are a great variety of this kind of substance and they can be rapidly derived. The structures or pharmacological properties of synthetic cathinones are similar to cocaine or methamphetamine, thus they were often abused and had a great impact on personal health and social stability. In order to further evaluate the abuse potential of synthetic cathinones and its mechanism of addiction, the preclinical dependence evaluation and related mechanisms of various animal models are reviewed from the aspects of self-administration, drug discrimination and conditional place preference.
To study the pharmacokinetic characteristics of metformin hydrochloride sustained-release tablets (0.5 g/tablet) in healthy volunteers, and to evaluate the bioequivalence of the two preparations.
A randomized, open, double-period, double-crossover trial was conducted. The tested reagent and reference reagent (Glucophage® XR®) for oral metformin hydrochloride sustained release tablets were applied to 36 healthy subjects in fasting/fed state. In this clinical trial, the validated HPLC/tandem mass spectrometry method was used to determine the concentration of metformin in human plasma of 14 time intervals in 48 h. The pharmacokinetic parameters were calculated.
After the volunteers were given tested and reference preparations in fasting/fed state, bioequivalence was evaluated by Cmax of metformin. The geometric mean ratio of Cmax was 101.12%, the 90%CI was 94.68%~108.00%, and the intra-individual variation was 16.36%. The geometric mean ratio of AUC0-t was 100.18%, the 90%CI was 95.13%~105.51%, and the intra-individual variation was 12.85%. The geometric mean ratio of AUC0-∞ was 101.06%, 90%CI was 95.86%~106.54%, and intra-individual variation was 13.11%. The geometric mean ratio of Cmax was 94.45%, the 90%CI was 90.13%~98.97%, and the intra-individual variation was 11.39%. When the AUC of metformin was used to evaluate the bioequivalence of the tested and reference preparations, the geometric mean ratio of AUC0-t was 103.21%, the 90%CI was 100.27%~106.24%, and the intra-individual variation was 7.04%. The geometric mean ratio of AUC0-∞ was 103.24%, 90%CI was 100.31%~106.26%, and intra-individual variation was 7.01%.
Both preparations were bioequivalent in fasting/postprandial status. The liquid chromatography-tandem mass spectrometry (LC-MS/MS) used in this study was accurate, rapid, sensitive and precise, providing theoretical reference for clinical safe drug use.
To evaluate the bioequivalence and safety of dexlansoprazole sustained-release capsule in healthy subjects on fasting and postprandial state.
A random, open, four-cycle, two-cross and single-dose design was adopted. Healthy subjects were grouped to either fasting or postprandial group (n=30 in each group). The concentrations of lansoprazole at 15 different time points after oral test or reference preparation (Dexilant®) were determined by high-performance liquid chromatography-tandem mass spectrometry. Average bioequivalence (ABE) method was adopted. The bioequivalence was evaluated using mixed effect model by Phoenix WinNonlin (Pharsight Corporation, Version 6.4) and confidence interval method. Adverse events (AE) were monitored during the whole test.
Thirty subjects completed the test in each of fasting or postprandial group. The average age of the subjects was 38.90±10.31 in fasting group, the ratio of male to female was 1∶1.31. The geometric average ratios of tested Cmax, AUC0-t and AUC0-∞ were 102.44%, 103.20% and 103.09%, and the 90% confidence intervals were 93.92%~111.74%, 98.57%~108.03% and 98.32%~108.09%, respectively. The average age of the subjects was (41.30±11.12) years in postprandial group, and the ratio of male to female was 1∶1.50, with the standard deviation Swr of each individual less than 0.294. The geometric average ratios of Cmax, AUC0-t and AUC0-∞ were 101.04%, 101.83% and 101.49%, with the 90% confidence intervals 95.76%~106.60%, 98.43%~105.35% and 97.90%~105.22%, respectively. The most common AE (≥2%) occurred during the experiment mainly included diarrhea, abdominal pain, and nausea. The unanticipated AE correlated with the test were T wave lowland (4, 6.67%), urine ketone body raised (1, 1.67%) and tachycardia (1, 1.67%). All AEs were not treated and recovered to normal. No serious adverse events (SAE) occurred.
Two formulations of dexlansoprazole sustained release capsules are bioequivalent and safe.
LPS induces RAW264.7 cells to become an inflammation model, and uses transcriptomics and proteomics techniques to explore the anti-diabetic chronic inflammation mechanism of berberine.
After RAW264.7 cells induced by LPS (0.1 μg·mL-1) were incubated with berberine (1 μg·mL-1), protein and RNA were extracted, and proteomics and transcriptomics analysis were performed. Proteins and genes that were differentially expressed were found, and gene ontology (GO) enrichment analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis were performed. STRING was used to draw interaction diagrams (PPI) to perform real-time fluorescence quantification of common differentially expressed proteins and genes PCR for verification.
By comparing the model group with the berberine group, there are a total of 1 801 differentially expressed genes in transcriptomics, and 11 differentially expressed genes, such as Pdia4, Itgam, Hsp90b1, Prdx5, Pdia6, Myc, Fosl1, Il10, Ccl2, Lpin2 and Pik3r2, are related to inflammation. Proteomics obtained a total of 83 differentially expressed proteins, and 10 differentially expressed proteins were found, including Hsp90b1, Pdia6, Prdx5, Pdia4, Itgam, Stat1, Pgm2, Ptgs1, Nos2, Actb, are related to inflammation. There are 5 common differentially expressed proteins and genes.
Berberine may achieve anti-inflammatory effects by reducing the release of inflammatory factors, while reducing Hsp90b1, Pdia6, Prdx5, Pdia4, Itgam, PTGS1, NOS2 and IL-10, and increasing the production of Pik3r2 and LPIN 2 genes to further relieve abnormal metabolism and insulin resistance as well as reducing oxidative damage to the endoplasmic reticulum to treat diabetes.
To explore the non-clinical safety evaluation method of Traditional Chinese medicine in juvenile rats, and observe the 4-week toxicity of Children Fengye Kechuanping Mixture, so as to provide reference for clinical medication in children.
A total of 120 juvenile SD rats were randomly divided into 4 groups according to bodyweight, with 30 rats in each group, half male and half female. Four groups were solvent control group, Children Fengye Kechuanping Mixture low (extract 7.0 g·kg-1), medium (extract 14.0 g·kg-1) and high (extract 22.5 g·kg-1) dose groups. Each group was given the medication once a day by gavage. PND21 were given for 4 weeks in total, and the solvent control group was given the same amount of deionized water. General status, bodyweight, food intake, growth and development, hematology, blood biochemistry, coagulation, urine, immunity, hormones, organs and histopathological changes were detected.
In high-dose group, the weight, food intake, hematological indexes (RET, RET% increase), organ weight or coefficient (thymus decrease, liver increase) changed. Growth retardation was observed in male juvenile rats (manifested as decreased top hip length, shortened tibia length, increased tibia total density and cortex density). No obvious toxic target organs were observed. The effect of the above expression in juvenile male rats was more obvious.
The safe dose of Children Fengye Kechuanping Mixture was 7.0 g·kg-1 (low dose, equivalent to raw dose 79.8 g·kg-1), 2.5 times of the equivalent dose and 14.9 times of the clinical dose in juvenile SD rats given by gavage for 4 weeks.
To prepare and calibrate the 5th batch of national standard reference for human menopausal gonadotropin (HMG).
Taking WHO 5th batch of international standard 10/286 as reference, the biological potency of the 5th batch of HMG national standard was determined by the method of 1216 follicle stimulating hormone assay and 1217 luteinizing hormone assay in Chinese Pharmacopeia (ChP, Volume Ⅳ, 2015 edition) in 6 laboratories. According to the parallel line measurement method of quantitative response in the biometric method 1431 in ChP (Volume Ⅳ, 2015 edition), BS2000 software was used to calculate the biological potency and conduct the combined calculation.
The biological titer FSH and LH of the 5th batch of HMG national standard products were identified to be 220 IU·ampoule-1 and 203 IU·ampoule-1 after collaborative calibration.
The candidate of HMG can be used as the 5th batch of HMG national standard for biological titer determination of HMG and related preparations.
To develop a rapid, robust and sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method for the determination of methylnaltrexone in human plasma.
The plasma samples were pretreated by filtering using solid-phase extraction (SPE) with a weak cation-exchange cartridge. The filtrate samples were separated on an Ultra PFP Propyl column (100 mm×2.1 mm, 5.0 μm) using 20 mmol·L-1 ammonium acetate (containing 1% formic acid) in water-acetonitrile (15∶85, v/v) as mobile phase and methylnaltrexone-d3 as the internal standard (IS). The flow rate was set at 0.4 mL·min-1. Methylnaltrexone and IS were ionized with an ESI source and MRM mode was applied and operated in positive ion mode. The detected ions were m/z 356.3→284.2 and m/z 359.3→287.1, respectively.
The linear range of the developed method was 0.1~120 ng·mL-1, with the lower limit of quantification being 0.1 ng·mL-1. The intra-day and inter-day precisions of the method were less than 7.2% across three validation runs, and the accuracy ranged 94.5%~100.7%. The extraction method using SPE reached a mean recovery of 81.4% for methylnaltrexone, and the mean normalized matrix effect was 99.1%. This method was successfully applied for the pharmacokinetic study of subcutaneous injection of methylnaltrexone bromide in 12 healthy volunteers.
This LC-MS/MS method is proven sensitive, rapid and reproducible, and meets the regulatory requirements of biological analysis.
To evaluate the analgesic and adverse effects of pregabalin after laparoscopic surgery.
Pubmed, Embase, Cochrane library, China Knowledge Network, Wanfang database and VIP database were searched for randomized controlled trials (RCT) that investigated pregabalin analgesa in adult patients undergoing laparoscopic surgery from inception to October 2019. RevMan 5.3 was used to perform analysis.
Eighteen RCTs with a total of 1169 subjects were included. Pregabalin was associated with a significant reduction in pain scores and opioid consumption at 24 h compared with placebo (MD=-8.34 mm, 95%CI: -11.68~-4.99, P<0.001 and MD=-5.88 mg, 95%CI: -7.66~-4.11, P<0.001). Patients receiving pregabalin had less postoperative nausea and vomiting compared with placebo (RR=0.75, 95%CI: 0.62~0.92, P=0.006). Visual disturbance was more common in pregabalin group compared with placebo group (RR=2.86, 95%CI: 1.33~6.18, P=0.007). There was no significant difference in the incidence of dizziness and sedation between the two groups (RR=1.08, 95%CI: 0.82~1.42, P=0.59; RR=2.41, 95%CI: 0.44~13.17, P=0.31).
Perioperative administration of pregabalin may decrease pain scores, opioid consumption, nausea and vomiting when used in different types of laparoscopic surgery. Single preoperative dose is recommended to reduce the occurrence of visual disturbance.
To quantitatively evaluate the efficacy, safety, and economic characteristics of tofacitinib for the treatment of rheumatoid arthritis (RA) patients by using the method of health technology assessment (HTA) and to provide evidence for medication selection and decision making based on the actual application of tofacitinib in clinical practice.
The HTA reports, systematic reviews/Meta analyses, and pharmacoeconomic researches published before May 31, 2019 were systematically searched. The databases and websites we searched included HTA official websites, English databases (PubMed and the Cochrane Library), and Chinese databases such as China Knowledge Network (CNKI), Wanfang and Weipu.
No HTA reports, but 21 Meta-analyses and 3 economic studies were included in this study. The results show that tofacitinib alone or combined with methotrexate treatment can clearly improve the efficacy of ACR, HAQ scores and other indicators of patients with RA, while the incidence of adverse events such as severe infections did not significantly increase. It can bring higher quality of life to patients with lower cost.
Tofacitinib and biologics are similar in efficacy and safety, and can improve patient medication compliance with a lower cost.
To compare the economics of prefilled syringe vs. injection of propofol medium and long chain fat emulsion, and to evaluate the satisfaction of dispensers.
Adopting simulated field test method, five dispensers used prefilled syringe or injection to prepare propofol medium and long chain fat emulsion in the Pharmacy Intravenous Admixture Services. The time saving was compared, and cost minimization analysis was conducted to evaluate the economics. The satisfaction of dispensers was investigated with a questionnaire survey, and the scores from 1 to 5 stand for being very dissatisfied to very satisfied.
Prefilled syringes shortened the time for preparing a single propofol by at least (40.20±5.15) s, P=0.000 1, and reduced the preparation cost in a single operation by at least (12.18±0.74) RMB, P<0.000 1. The score was (1.8±1.64) points higher in using prefilled syringes for the overall satisfaction (P=0.071), (2.0±1.58) points higher for improving the safety of dispensers (P=0.047), (2.2±1.64) points higher for facilitating the preparations (P=0.040), and (1.4±1.52) points higher for avoiding preparation errors (P=0.11).
It significantly reduced costs and shortened the preparation time to prepare propofol medium and long chain fat emulsion prefilled syringes. Dispensers were more satisfied with prefilled syringes.
This study aims to analyze the cost-utility of the add-on of Dengzhan Shengmai (DZSM) capsule with standard medical therapy and standard medical therapy alone in secondary stroke prevention.
A Markov model was constructed based on the societal perspective and the costs and health unities were simulated for a time horizon of 5 years. The model included 4 health states, included healthy, recurrent stroke-independent (mRS0-2), recurrent stroke-dependent (mRS3-5) and death. Clinical data and utilities for the modelling analysis were obtained from published literatures. Direct costs included medication costs obtained from public database, and costs for hospitalization, post-discharge rehabilitation service, and secondary prevention were sourced from published literatures. 2019 inflation-adjusted costs were calculated using Consumer Price Index (CPI) for medical care. Indirect costs included loss of salary for patients and their families caused by the disease which were derived from China statistical yearbook.
Base-case analysis results showed that the incremental costs of DZSM group (29 284 RMB) over 5 years were higher than the control group (21 551 RMB). The incremental health utilities of DZSM group (3.91 QALYs) over 5 years were also greater than the control group (3.81 QALYs). The incremental costs of the two group were 7 734 RMB, while the incremental utilities were 0.1 QALYs. The incremental cost-utility ratio was 74 479 RMB/QALY, which equals to approximately 1.05 times of GDP per capita and less than 3 times of GDP per capita, indicating that the add-on of DZSM capsule with standard medical therapy were more cost-effective. Sensitivity analyses revealed robust results.
Compared to standard medical therapy alone, the add-on of DZSM capsule has economic advantages in secondary stroke prevention.
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