ArchiveTo study the development process, current situation and specific requirements of drug registration based on e-CTD format in the United States, and to provide some reference for the construction of e-CTD channel for drug registration in China.
A literature review was used to review the regulatory process of e-CTD implementation in the United States, and the data of e-CTD application and total electronic data application were compared and analyzed. To explore the similarities and differences between the traditional registration declaration format and e-CTD format in terms of organization, data requirements, application process and data review, the specific changes were analyzed.
In the process of e-CTD implementation, the United States improved and optimized the submission process and approval process by constantly issuing technical guidelines and paid attention to the training of technical personnel and protected data security. On the one hand, it is suggested that Chinese regulatory agencies improve the guidelines for drug registration application based on e-CTD format as soon as possible, increase policy support such as priority review and approval, and strengthen e-CTD knowledge training for registration personnel in enterprises and review centers. On the other hand, strengthen e-CTD knowledge training for registered personal of enterprises and agencies, enterprises should change their research and development ideas, carry out the QbD concept, formulate a registration operation team suitable for their own development needs, and actively participate in international drug registration to accumulate experience in order to promote the application of e-CTD in enterprises
The establishment of impurity limits is one of the key factors in the establishment of drug product specifications. Reasonable impurity limits are very important for the safety and controllability, and closely related to the drug quality. Taking several typical impurities as examples, this paper systematically expounds and demonstrates the determination approach of the maximum daily exposure dose (PDE), the conversion method in specific drugs, and the limit determination of impurities in products, which can help better understand and implement ICH-related guidelines. This paper provides reference for drug developers to formulate product specification.
Compound amino acid injection, as the source of nitrogen in parenteral nutrition, is administrated to patients with compromised gastrointestinal function or those whose nutritional needs cannot be met through gastrointestinal tract. Therefore, compound amino acid injection plays an important role in nutritional therapy and support. The active pharmaceutical ingredients of compound amino acid injection are complicated, and some amino acids are sensitive to light, heat, and oxygen, etc., which brings certain challenges to the research and development of such drugs. Based on literature research and evaluation experience in recent years, this paper discusses some issues which may need to consider during the development of generic drugs of compound amino acid injection from the aspects of API quality control, formulation design, manufacturing process development, quality research and control, selection of container enclosure system and stability studies in order to provide reference for researchers in this field.
Aizijin is a traditional Tibetan medicine in China from Corydalis hendersonii Hemsl. and Corydalis mucronifera Maxim. with a long history of application and its property is mainly cool and tastes bitter. It is commonly used to treat enteritis, angiitis, "Mubu" and other diseases in Qinghai-Tibet Plateau. Modern research shows that Aizijin has rich chemical components like alkaloids, flavonoids, pentacyclic triterpenoids and other components and shows antipyretic, analgesic, anti-inflammatory and antioxidant effects, which can be used in the treatment of high altitude polycthemia (HAPC). Through literature research, we reviewed the chemical components and pharmacological effects of Aizijin and forecast its future development, which provides a scientific basis for the further development and resource conservation of Aizijin.
Histopathology data of toxicology studies during nonclinical safety evaluation of drugs are critical during the drug discovery and development process that is necessary for regulatory bodies to assess drug-related toxicity in laboratory animals and its impact on human safety in clinical trials. Artificial intelligence (AI) has been widely used in clinical medical practice with progress in the whole slide image (WSI), digital pathology and algorithms. However, the progress of machine learning (ML)-in particular, deep learning (DL)-has been rather slow in toxicologic pathology of nonclinical toxicology studies. This paper briefly reviews the role of toxicologic pathology in drug discovery and development, overview of AI and approaches of DL, applications of approaches of DL in toxicologic pathology, as well as the challenges in implementation of approaches of DL in toxicologic pathology, in order to provide reference for implementation of approaches of DL in toxicologic pathology for toxicology studies during nonclinical safety evaluation of drugs in China.
The phosphorylation of serine 209 of eukaryotic translation initiation factor 4E (eIF4E) by mitogen-activated protein kinase-interacting kinase (MNK) is closely related to the process of translation initiation of tumor-related mRNA, and this process plays an important role in tumor occurrence and metastasis. Since MNK has gradually become an important antitumor target, the development of MNK small-molecule inhibitors has attracted the attention of researchers in recent years. Therefore, we reviewed the research progress of MNK small-molecule inhibitors by summarizing the structure and signal transduction mechanism of MNK.
Salt-inducible kinases (SIKs) belong to the AMP-activated protein kinase (AMPK) family, which mainly regulates the cytosolic-cytoplasmic distribution of cAMP-response element binding protein transcriptional coactivators (CRTCs). They exert regulatory effect on the synthesis of CRTC-CREB complexes, which indirectly affect the transcription and expression of CREB target genes and various physiological processes, such as energy metabolism, cell cycle progression and apoptosis. Previous researches related to SIKs have focused on peripheral system diseases, including tumors, hypertension and gluconeogenesis. In recent years, increasing studies have begun to explore the link between SIKs and central nervous system diseases with abnormal levels of SIKs present in diseases such as depression, sleep disturbance, epilepsy and Alzheimer's disease. It suggests that dysregulation of SIKs signaling is involved in the pathological processes of these diseases and has the potential to become new therapeutic targets in these diseases. This article reviews the role and regulatory mechanisms of SIKs in depression, sleep disturbance and other neurological diseases.
Clinical trials is a scientific experimental activity that needs thorough plan and strict execution. Investigators often expect to complete the trial according to the study plan. However, due to the uncertainty of disease mechanisms, the diversity of patients, and the complexity of interventions, trials usually cannot be executed exactly according to the established protocols. A comprehensive review of the implementation of registered clinical trials reveals that such situations are not uncommon and commonly include: the aim of the clinical trials is apparent inability to complete thus requiring termination of the trials; unexpected events, such as adverse reactions, policy changes, etc., leading to suspend the trial and adjust the trial protocol. However, research on this issue is limited, and there is no definite answer on the scientific understanding, reason analysis, and plan design. In this paper, we comprehensively review the factors related to the suspension and termination of clinical trials and try to propose a solution.
HPLC was used to establish the methods for the determination of harmaline (HM) and the derivative 9-butyl-1-methyl-N-(2-hydroxy) ethyl-β- carboline-3-formamide (No.: H-2-104) in rat blood samples in order to evaluate repeated dosing toxicokinetics (TK).
The Wistar rats were randomly divided into HM low, medium, and high-dose groups and H-2-104 low, medium, and high-dose groups (35, 70, 140 mg·kg-1) with eight rats in each group. Repeated dosing toxicity experiments were conducted to investigate the toxicokinetic profile of HM and H-2-104 in rats 28 days after the first dose to the end of administration and the kinetic parameters were calculated.
Both HM and derivative H-2-104 could be detected with good linearity in the range of 66.67~500 ng·mL-1. The specialized properties, accuracy, precision, extraction recovery, and stability of the proposed method were in accordance with the requirements for the determination of biological samples. After the administration of HM, the Cmax and AUC0-t in rats were (301.78±67.24) ng·mL-1, (234.18±98.35) ng·mL-1 (low concentration); (478.65±99.74) ng·mL-1, (710.03±208.93) ng·mL-1 (medium concentration); (721.51±107.52) ng·mL-1, (819.61±310.54) ng·mL-1 (high concentration). After the administration of H-2-104, the Cmax and AUC0-t in rats were (234.84±102.03) ng·mL-1, (198.67±38.88) ng·mL-1 (low concentration); (298.73±87.52), (676.55±210.83) ng·mL-1 (medium concentration); (411.81±123.71), (1 004.86±426.05) ng·mL-1 (high concentration). After administration, Tmax of the two compounds was shorter and both drugs were eliminated within 4 hours.
The first and last Cmax and AUC0-t of HM and derivative H-2-104 at each dose increased disproportionately with dose and were positively correlated with dose, exhibiting nonlinear kinetics. This study provides preliminary elucidation of the in vivo toxicokinetic behavior of HM and derivative H-2-104 in rats, and the experimental results provide support and reference for their subsequent studies.
The chemical pattern recognition technology was used to analyze the HPLC characteristic fingerprints data of Poria, screen the differential quality markers and perform quantitative analysis, so as to provide scientific basis for quality evaluation of Poria.
Welch Ultimate Plus C18 chromatographic column (250 mm×4.6 mm, 5 μm) was used. Acetonitrile (containing 0.2% tetrahydrofuran)-0.1% phosphoric acid aqueous solution with gradient elution was used as mobile phase. The fingerprint of Poria was established with detection wavelength set at 222 nm, flow rate at 1 mL·min-1, column temperature at 30 ℃, injection volume at 10 μL. The differential quality markers were identified by similarity analysis, principal component analysis (PCA), cluster analysis (CA) and orthogonal partial least squares-discriminant analysis (OPLS-DA). The quantitative research was carried out in accordance with the requirements of "Guidelines for Validation of Analytical Methods" in Chinese Pharmacopoeia.
The similarity of 15 batches of Poria was between 0.935~0.998. Eight common peaks were calibrated and 6 were identified; The samples were classified according to the origins from PAC results, which is consistent with CA result. Pachymic acid was screened as the differential quality marker of Poria by OPLS-DA. The established method for the determination of pachymic acid was stable, reliable, durable, which meets the requirements of the Pharmacopoeia.
The methods of characteristic fingerprint combined with chemical pattern recognition technology can effectively screen the differential quality marker of Poria from different regions, providing a reference for the establishment of quality standards for Poria.
To establish an analytical method for determination of the content and dissolution of aprepitant, prepare aprepitant solid dispersion by three different preparation methods (hot-melt extrusion, solvent-melt method and spray drying method), and investigate the effects of different processes on the physical stability of the solid dispersions.
The effects of different preparation processes on the stability of aprepitant solid dispersions were measured in terms of water content, moisture attraction, residual microcrystals, aprepitant content, related impurities, and in vitro release.
Among the three different processes, the aprepitant solid dispersion prepared by hot-melt extrusion had low water content, poor moisture attraction, drug in amorphous form, good in vitro dissolution behavior, able to dissolve and release in acid solution, resistant to crystallization and precipitation behavior due to pH change and maintained high supersaturation after transit to the intestine.
Hot-melt extrusion is the optimal preparation method for solid dispersions composed of crystallization inhibitor HPMCAS and dissolution enhancer PVP K30.
In order to improve the oral bioavailability of curcumin, curcumin nanocrystalline suspension (Cur-NCS) was prepared by the high-pressure homogenization method in "top-down" method. Its physical properties, in vitro release, in vivo bioavailability and anti-inflammatory activity were studied.
The prescription and process parameters were optimized using particle size and zeta potential as evaluation indexes; the sample morphology was characterized by transmission electron microscopy, the in vitro release of curcumin nanocrystallines suspension was determined by HPLC, and the blood concentration of curcumin in rats was measured by LC-MS/MS; the anti-inflammatory activity was investigated in RAW264.7 inflammatory cell model, and curcumin was investigated in a mouse model of bronchial asthma airway inflammation nanosuspension on the therapeutic effect of curcumin on airway inflammation in mice.
Preparation process: curcumin was sheared at high speed for 2 min at 16 000 r·min-1 and cycled 40 times at 800 bar. Prescription: curcumin dosage was 0.2%, TPGS dosage was 0.20% and soy lecithin dosage was 0.16%; the cumulative drug release of API and Cur-NCS was 11.67% and 27.44%, respectively. After gavage in rats, Cur-NCS bioavailability was increased by 1.86-fold after gavage in rats. In an in vitro inflammatory cell model and in vivo bronchial asthma mouse model, Cur-NCS significantly inhibited the expression of inflammatory factors NO, IL-6, TNF-α and the levels of MDA, IgE and ICAM-1, and increased the expression of IL-10 and the level of SOD.
The identified preparation process and prescription can meet the preparation requirements of curcumin nanosuspension, and the in vitro release, in vivo bioavailability and anti-inflammatory activity are significantly better than those of API, and curcumin nanosuspension can provide ideas for subsequent dosage form studies.
To prepare photothermal lipid membrane coated Escherichia coli and study the properties.
The photothermal lipid membrane (LMI) was prepared by thin film dispersion method, and the electrostatic adsorption method was used to coat Escherichia coli with the lipid membrane (LMI@Ec). The size and potential of LMI@Ec were analyzed by laser scattering particle size analyzer, the morphology of E.coli and LMI@Ec was observed by transmission electron microscopy and laser confocal microscopy, and plate counting method was used to detect cell viability of LMI@Ec. In addition, the effect of protein expression of LMI@Ec was evaluated by polyacrylamide gel electrophoresis, and the photothermal effect of LMI@Ec was detected by Infrared Photothermal Imager.
LMI@Ec had a smooth surface with the average particle size of (1 990.5±132) nm and the potential of -(5.09±0.52) mV. The coating of the lipid membrane had little effect on the activity of E.coli. Although the bacterial activity decreased after laser irradiation, the growth curve recovered to the same level as wild bacteria after 10 h of temperature gradient culture in LB medium. LMI@Ec had well photothermal properties and can normally express protein. In vitro cytotoxicity experiments showed that LMI@Ec under 808 nm laser irradiation presented enhanced antitumor effect on B16F10 and HepG2 cells.
The successful preparation of LMI@Ec provides a new research direction for the subsequent in-depth study of bacteria-mediated disease treatment.
Different levels of genotoxic impurities 1-methyl-4-nitroso piperazine (MNP) and 1-methyl-4-nitroso piperazine (CPNP) were detected in rifampicin and rifapentine capsules. In this study, the nitrite ions in rifampicin and rifapentine capsules were determined by solid phase extraction-ion chromatography to explore the relationship between the content of nitrite ions and the formation of above genotoxic impurities.
The method of solid phase extraction-ion chromatography used for nitrite determination was established and validated.
Nitrite ion was not detected in rifampicin and rifapentine capsules with different levels of MNP and CPNP.
It is speculated that the origin of MNP and CPNP in rifampin and rifapentine capsules was not from nitrite ion, but derived from oxidative degradation of API.
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