Latest ArticlesThe study evaluates the lipolysis rate and extent of type Ⅲ lipid formulations using testosterone undecanoate as a model drug after digestion with in vitro lipolysis model, and studies the digestive regularity with optical microscope and electrical conductivity. The results showed that for testosterone undecanoate type Ⅲ lipid formulations with castor oil as oil phase and Transcutol HP as latent solvent, the lipolysis rate and extent were increased with the increase of oil phase proportion and were decreased with excessive proportion of surfactant, in which can see liquid crystal phase during lipolysis process. The lipolysis rate of type ⅢB lipid preparations with different surfactant were ordered as Labrasol > Tween 80 > Cremophor EL, but the rate of type ⅢA is different in quick digestion phase and slow digestion phase. The lipolysis extent of type Ⅲ lipid formulations with different surfactant were ordered as Cremophor EL > Tween 80 > Labrasol. These may be related to the digestive effect of pancreatic lipase on different surfactants. This study implied that the lipolysis rate and extent of type Ⅲ lipid formulations are greatly influenced by the proportion of oil phase and surfactant, and the surfactant structure. These factors will affect the in vivo digestion and should be taken into account when screening type Ⅲ lipid formulations.
In this study, artemether (ARM)-loaded mixed micelles (MM) composed of the sodium glycocholate (SGC) and soybean lecithin (SL) were prepared by film dispersion method. The effects of hydration medium, SL mass ratio and total concentration of excipients on the solubilization of ARM were investigated and the stability of MM was evaluated. Results showed that the particle size distribution of SGC-SL-MM prepared by phosphate buffer solution (PBS, pH 7.4, 0.05 mol·L-1) was uniform, with an average size of 3.58 ±0.14 nm and the polydispersity index (PDI) value was 0.16 ±0.04. The solubility of ARM increased significantly from 0.64 ±0.04 mg·mL-1 to 13.7 ±0.13 mg·mL-1 along with the concentration of total excipient increasing from 1.0% to 30.0% (w/w). The calculated results of Arrhenius parameter and storage stability showed that the degradation rate constant of ARM in MM was smaller than that in acetonitrile-PBS (pH 7.4) at either 37 ℃ or 60 ℃. The experimental ARM-MM was clear after storing for two months at 25 ℃ and the degradation of ARM was less than 7.0%. In conclusion, the SGC-SL-MM can not only improve the solubility of ARM in aqueous solution, but also improve its chemical stability in aqueous solution at low temperature.
Methotrexate (MTX) injection has a short half-life and significant toxic side effects. In order to overcome the demerits of MTX injection, MTX@COF was prepared for subcutaneous injection by loading MTX in crosslinked cyclodextrin metal-organic framework (COF) in this study. The cationic lipid material (2, 3-dioleoyl-propyl)-trimethylamine (DOTAP) was then coated on the MTX@COF surface by solvent evaporation. Different surface charge characteristics were observed in the coated MTX@COF@DOTAP with no significant change in particle morphology. The in vitro release behaviors of sustained-release particles were investigated in water and phosphate buffer (pH 7.4), and the in vivo release characteristics were evaluated for pharmacokinetics in rats. The in vitro release results showed that the cumulative release of MTX, MTX@COF and MTX@COF@DOTAP within 6 h was 92.70%, 36.31% and 18.19% in water, respectively; the cumulative release of MTX, MTX@COF and MTX@COF@DOTAP within 4 h was 90.82%, 79.37% and 58.30% in phosphate buffer, respectively; the results showed that MTX@COF can significantly delay the release of MTX, the modification to MTX@COF by DOTAP can further delay the release of MTX. Pharmacokinetic studies in rats showed that the mean retention time [MRT(0-t)] and the time to peak (Tmax) of the subcutaneous injection of MTX@COF@DOTAP group were significantly prolonged compared with the MTX@COF group and the MTX group. The area under the concentration-time curve [AUC(0-t)] of the MTX@COF@DOTAP subcutaneous injection group was 1.8 times high as that of the MTX group. In this study, MTX@COF@DOTAP particles had a certain sustained-release effect, and could prolong the bioavailability of MTX by subcutaneous injection, which provided a new idea for the development of new MTX dosage forms.
Ferulate 5-hydroxylase (F5H) is a key enzyme involved in the phenylpropane metabolism pathway. Based on our previous transcriptome sequencing study, F5H played a negative regulatory role in glycyrrhizic acid (GA) biosynthesis. Therefore, in this study we cloned the F5H gene and investigated its regulatory effect on GA accumulation through gene overexpression and knockout. F5H was cloned from Glycyrrhiza glabra L. (GenBank Accession No. MK882511). A plant binary expression vector pCA-F5H was constructed by inserting F5H into pCAMBIA1305.1 at Spe Ⅰ and Bgl Ⅱ sites. The sgRNA sequences were designed based on the first exon of F5H. The CRISPR/Cas9 gene editing vector pHSE-F5H was constructed by inserting F5H sgRNA into pHSE401 at two Bsa Ⅰ sites. PCA-F5H and pHSE-F5H were transfected into Agrobacterium tumefaciens ATCC15834, which was used to induce hairy root overexpressing or knocking out F5H with licorice hypocotyl as explants. At the same time, wild type and negative control hairy roots were also generated. UPLC was used to assay the GA content in different hairy root lines, and results showed that the GA content in hairy root lines knocking out F5H was significantly higher, whereas in hairy root lines overexpressing F5H GA content was lower than that in the wild-type and negative control. In this work, through a reverse genetics strategy, the negative regulatory effect of F5H on GA biosynthesis was confirmed through gene overexpression and knockout. This work will lay a foundation for further elucidation of the molecular regulatory network of GA biosynthesis.
In the research and development of new drugs, it is very important to investigate the in vitro metabolism of candidate drugs. Traditional models such as liver microsomes have many limitations, while the in vitro model of recombinant human drug metabolizing enzymes is considered as an important and useful approach because of its convenient access, stable activity and low cost. In this study, six major human UDP-glucuronosyltransferases (UGTs) genes (UGT1A1, 1A3, 1A4, 1A6, 1A9 and 2B7) were cloned from human liver cDNA and heterologously expressed in Saccharomyces cerevisiae and baculovirus-infected insect cell. UGT1A1, 1A3, 1A6 and 1A9 were successfully expressed in yeast and showed glucuronidation activity against a variety of different structural types of substrates, but their activities were low. All six UGTs were successfully expressed and exhibited significantly improved glucuronidation activity when Trichopolusia ni cells BTI-TN5B1-4 (High Five) were used as the host. The recombinant human UGTs expressed in insect cells can catalyze the glucuronidation of their specific substrates, and the glucuronidation products were synthesized at milligram-scale with yields of 13%-66% for the first time, of which the structures were identified via MS, 1H NMR, and 13C NMR spectroscopic analysis. Above all, the recombinant human UGTs yeast and insect cell expression systems constructed in this study can be used for in vitro metabolism evaluation in the early stage of new drugs research and development, and also provide a new tool for the synthesis of glucuronide metabolites.
Based on the "requirements on the submitted documents for consistency evaluation of generic oral solid dosage forms of chemical drugs" and relevant guidance, this article summarized and formulated the decision tree of in vitro consistency evaluation of oral solid generic drugs, discussed the differences and common problems of in vitro evaluation research projects under different conditions, selective analyzed the technical requirements and concern problems of unconventional research projects, and proposed corresponding recommendations for concern problems, in order to provide more references for the follow-up study on consistency evaluation of oral solid generic drugs.
In recent years, targeted therapy has become the standard treatment for advanced non-small cell lung cancer (NSCLC), but this treatment method has very limited effect on patients with epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutation. This insertion mutation is the third most common mutation in EGFR. It shrinks the drug binding pocket and gives tumors inherent resistance to available EGFR tyrosine kinase inhibitors (TKIs), resulting in the limited efficiency of the first and second generation of EGFR tyrosine. So far, no targeted therapy has been approved for NSCLC patients with EGFR exon 20 insertion mutations, and there are still no drugs that have met clinical needs. In this case, new treatment strategies using new EGFR TKIs or bispecific antibodies may establish new treatment standards for these patients in the future. In this review, we will summarize all relevant exon 20 insertions reported so far on the structure of EGFR and its influence on EGFR inhibitor sensitivity, as well as the treatment strategies of exon 20 insertions in NSCLC patients, hoping to be a clinical treatment for reference.
Pneumonia caused by SARS-CoV-2 has seriously threatened human life and health worldwide and caused a large number of deaths. Viral infection and acute inflammation are important causes of death, so it is particularly important to combine antiviral therapy with anti-inflammatory therapy. Glycyrrhizic acid, the main component of the glycyrrhizic root extract, has a wide range of pharmacological effects as well as high efficiency and low toxicity, its preparation has been widely used in the treatment of chronic hepatitis and other diseases. Glycyrrhizic acid can regulate the expression and release of a variety of cytokines and play a significant anti-inflammatory effect. At the same time, glycyrrhizic acid also showed significant inhibition towards a variety types of viruses. Therefore, the potential application of glycyrrhizic acid as COVID-19 treatment should be explored.
Nucleocytoplasmic transport is the basic cellular activity of eukaryotic cells, which plays a role in cell physiological and pathological processes. A large amount of evidences indicate that impaired nucleocytoplasmic trafficking has emerged as a mechanism contributing to the pathology of neurodegenerative diseases. The regulation of nucleocytoplasmic transport is crucial to elucidate the pathogenesis and intervention in the neurodegenerative diseases. This article summarizes the evidences in disturbed nucleocytoplasmic transport of neurodegenerative diseases in the past two decades, further explores the directions and provides a theoretical basis for the pathogenesis and drug targets in neurodegenerative diseases.
Xanthine oxidase (XOD), catalyzing purine metabolism, is the key enzyme in uric acid (UA) biosynthesis, and becomes an important target for hyperuricemia treatment. The inhibition on XOD plays an important role in the treatment of hyperuricemia-related diseases, such as gout, as well as oxidative stress-induced tissue injury. Here, studies on the natural products with XOD inhibition are reviewed.
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