Edoxaban(1), an oral inhibitor of coagulation factor Ⅹ a(F Ⅹ a), is clinically used for the treatment of venous thromboembolism complicated by undergoing orthopaedic surgery of the lower limbs. According to retrosynthetic analysis, 1 is mainly composed of three key intermediates, namely tert-butyl [(1R,2S,5S)-2-amino-5-(dimethylcarbamoyl)- cyclohexyl]carbamate(2), 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid(3), and 2-[(5-chloropyridin- 2-yl)amino]-2-oxoethyl acetate(4). Among them, the synthesis of the cis-cyclohexanediamine fragment of 2 and the thiazole ring fragment of 3 is more difficult. The paper summarizes the schemes for the synthesis of cis-cyclohexanediamine fragments by azide salts(esters), photo-extension reaction, Burgess reagent and other starting materials, and the synthesis of the thiazole ring fragment by monocyanine and sulphur, Asinger reaction, Grignard reagent and trichloroacetophenonium salts, and briefly comments on the corresponding advantages and disadvantages.

Momelotinib(1), a Janus kinase 1/2(JAK1/JAK2) inhibitor, was synthesized via a new synthetic route in three steps. The cyclization of ethyl 4-acetylbenzoate(2), N,N-dimethylformamide dimethyl acetal(DMF-DMA) and urea was achieved successfully to give ethyl 4-(2-oxo-1,2-dihydropyrimidin-4-yl)benzoate(3), which was subjected to the amination with 4-morpholinoaniline(4) in the presence of (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(PyBOP) and 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU) to afford ethyl 4-[2-[(4-morpholinophenyl)- amino]pyrimidin-4-yl]benzoate(5). Compound 5 was subjected to the amidation with 2-aminoacetonitrile in the presence of air and potassium tert-butoxide to deliver the target product with purity of 99.5％ .This new synthetic route had fewer reaction steps and high overall yield(70％ based on 2).

Glioblastoma(GBM) is a highly malignant brain tumor with high disability and recurrence rate. Conventional treatment for GBM is prone to recurrence, and the prognosis of drug-resistant patients is unfavorable. Small interfering RNA(siRNA) can generate therapeutic effects by silencing specific genes and down-regulating protein expression, and can serve as a supplement to conventional treatment by inhibiting the development process of GBM. This review elaborates on the difficulties of siRNA delivery into the brain and the mechanism of GBM treatment by siRNA. Additionally, it summarizes the application of five non-viral siRNA delivery systems for GBM treatment, in order to provide a reference for the application research of siRNA in GBM treatment.

数据完整性一直备受全球制药界关注，因涉及产品质量，其监管要求不断提高。目前，中国、美国、英国和欧盟对 于数据完整性持续提出了监管新要求。文章分析了数据完整性的基本原则，归纳、总结了各国对于药品生产数据完整性的 要求，汇总了药品生产企业关于数据完整性缺陷方面的问题，进行举例和深刻剖析，并对生产设备、验证管理和记录管理 等涉及数据完整性的常见缺陷项整改措施提出建议，以期指导药品生产企业提高数据完整性管理。

Due to its high bioavailability and good patient compliance, pulmonary inhalation administration has demonstrated significant clinical application value in the treatment of lung disorders and even plays a role in systemic therapy. However, there are numerous obstacles to drug delivery because of the unique physiological structures of the lungs. Nano drug delivery system has been widely used in pulmonary inhalation administration for its special benefits. This paper suminarizes the pulmonary drug delivery barriers and several inhalable nano drug delivery systems in detail, in order to provide reference for future clinical studies of pulmonary inhalation preparation.

Bioequivalence studies of suspension-based nasal sprays are challenging tasks for generic drug developers. Researchers should not only conduct consistency studies on the dosage and formulation characteristics of excipients in accordance with the requirements of the guidelines, but also need to use analytical tools to determine the consistency of key quality attributes such as particle size and particle size distribution of active pharmaceutical ingredients. This study explored the application of morphologically-directed Raman spectroscopy in the study of particle size distribution of nasal suspensions. The method has been approved by the U.S. FDA for the studies that substitute bioequivalence of clinical endpoints, which is critical for cost reduction and faster development for consistency evaluation of suspension-based nasal spray products.

In situ gel is a novel formulation which is administered in solution and can rapidly occur phase transformation at the site of application to become semi-solid or solid gel. In addition, it can respond to the changes in external factors such as temperature, light, pH value, hydrophily/hydrophobicity, ionic strength. In situ gel has shown unique advantages in a variety of applications, including ophthalmic, nasal, oral, transdermal, injectable and vaginal routes, due to its excellent biocompatibility, bioadhesion ability, sustained- and controlled-release properties. In this paper, the advantages and disadvantages of traditional dosage forms and in situ gel are compared according to the characteristics of various routes of administrations. The research progress of in situ gel in above routes is introduced, and some approval in situ gel products are presented.

The droplet size distribution was measured by the laser particle size measurement system, while the spray pattern and plume geometry were measured by SprayVIEW laser imaging system. The spray performances of two kinds of suspension nasal sprays between the original drugs and the generic drugs were compared. Additionally, the consistency of spray performances between different batches of the samples from 4 companies(A, B, C, D) was analyzed in this study. The results showed that d(0.5) was in the range of 27 - 51 μm. The droplet size distribution results of the products from companies A and B, C and D were different. The intra- and inter-batch variabilities of the droplet size distribution of nasal sprays from companies A and D were less than those of the products from companies B and C, respectively. The spray area showed a signiffcant difference between the original drugs and the generic drugs. The plume geometry results of the products from companies A and B, C and D were similar. The cross section of the spray was nearly circular with elliptical rate of 1.13 to 1.41. The spray performance results of the products from the original drugs and the generic drugs were different. Therefore, it was necessary to strengthen the investigation on detection methods of the spray performances and comparison study of different products in the development of nasal spray products.

Inflammatory bowel disease(IBD) is a chronic intestinal inflammatory disease with an increasing incidence rate year by year, but its etiology is still unclear. And there is a lack of well-targeted and safe therapeutic drugs. In recent years, probiotics have shown large potential as a potential treatment strategy for the prevention and treatment of IBD. This paper elaborates on the mechanism of probiotics in the treatment of IBD, summarizes common probiotic species used in the treatment of IBD, and looks forward to the application of probiotics, aiming to lay a foundation for the research on probiotics in the treatment of IBD.

The oral delivery of peptide and protein drugs has received widespread attention in recent years, and how to overcome gastrointestinal physiological barriers and improve bioavailability is a key issue in their clinical applications. Mesoporous silica is an artificially synthesized nanoscale inorganic porous material. Due to the unique properties, such as controllable particle size, pore size, morphology, and surface chemistry, mesoporous silica has the potential to serve as an oral delivery carrier for peptide and protein drugs. This article reviews the main barriers that hinder the oral absorption of peptides and protein drugs, the characteristics, synthesis, surface modification methods, and some recent advances of mesoporous silica, hoping to provide new ideas for the application of mesoporous silica to oral delivery of peptide and protein drugs.

Periodontitis is a chronic infection of the periodontal tissue caused by the biofilm of dental plaque,
which can lead to tooth loosening, gum atrophy. Its main pathogenic bacteria include Porphyromonas gingivalis. Based on
the abundant blood vessels in the periodontal pocket, local delivery of antibacterial drugs can make drugs act directly on
the lesion site and improve the bioavailability. This paper focuses on introducing biodegradable local drug delivery systems
that have been marketed for the treatment of periodontitis, and summarizes the relevant drug prescriptions and preparation
processes, hoping to provide a reference for the development of new dosage forms for the treatment of periodontitis.

Nano spray drying is a mild and effective particle preparation technology. It innovatively adopts piezoelectric atomizing mechanism, laminar heating mode and electrostatic particle collection system, and has many advantages such as adjusting particle size, improving solubility, realizing surface modification. Nanoscale particles can be obtained with high output(90％ ) by this technology. The minimum sample volume processed by the nano spray dryer can reach milligram level. Starting from the development history and technical characteristics of nano spray drying technology, this paper introduces the structure and working mechanism of nano spray dryer, summarizes the formulation and process parameters affecting the properties of the obtained particles by nano spraying, and puts forward suggestions on their selection and optimization.

Covalent organic frameworks(COFs) have attracted great attention in the field of drug delivery due to their characteristics such as high specific surface area, uniform and adjustable pore size, and facile modification and functionalization. This review introduces the preparation methods of COFs, including template-mediated coprecipitation method, one-pot synthesis method and in situ doping method. More over, this review elaborates the structural design of COFs, including intelligent stimuli-responsive molecular design and surface modification. In addition, this review also outlines the applications of COFs in the field of delivery of antineoplastic, antibacterial and anti-inflammatory drugs, aiming to provide insightful perspectives to facilitate the rapid development of COFs-based drug delivery systems.

胶束制剂作为复杂制剂，能提高难溶性药物的载药量、改善药物体内药动学、提高药效、降低毒性，具有较高的临 床应用价值。然而，胶束制剂的技术壁垒高、研发难度大。目前，国内尚无胶束制剂的相关技术要求。该文参考胶束制剂 的国内外监管现状，结合实际审评工作经验，从聚合物辅料、临界胶束浓度、结构表征、释放度、体内释药行为和用法研 究方面，分析了胶束制剂质量研究的注意事项，为胶束制剂的开发和监管提供了参考。

Due to various physiological and anatomical barriers in the human eye, the bioavailability of topical ophthalmic preparations, such as eye drops, is less than 5％ . While the bioavailability of drug-eluting contact lenses can achieve 50％ , and the products have the dual functions of drug release and visual correction. This paper reviews the research progress of preparation methods, sterilization and quality evaluation of drug-eluting contact lenses. The advantages and disadvantages of different preparation methods in drug loading and release, as well as the critical functional attributes of drug-eluting contact lenses are emphasized, hoping to provide some references for promoting the clinical application of medicated contact lenses.

儿童是药物治疗的特殊群体，儿童与成人的生理特性和药物代谢特点存在差异。随着对儿童用药可及性的重视程度 不断加深，越来越多的儿童适宜制剂亟待开发；而儿童对制剂用辅料的安全性和适宜性有着特殊要求。文章综述了全球主 要国家和地区关于儿童制剂用辅料的监管政策和使用现状。尽管各国对儿童制剂用辅料出台了一些监管政策，但仍存在儿 童频繁暴露于不安全辅料、药品说明书中辅料信息缺乏、儿童制剂可用辅料信息少等问题。对此，文章提出完善安全性评 估体系、建立信息共享机制和加大创新辅料和创新技术研发的思路，以期促进儿童制剂用辅料的发展，为增进儿童的健康 和福祉作出贡献。

Microbial contamination is a major problem in the application of pharmaceutical purified water. Microorganisms can attach to solid surfaces and form biofilms by producing extracellular polymers, which can reduce the filtration efficiency of filtration units. They may also detach and enter the purified water distribution system, posing a risk to the quality and safety of pharmaceutical products. Therefore, it is necessary to explore methods for optimizing the current pharmaceutical purified water system process from the perspective of the three major factors influencing microbial growth in such systems: the surface area of the filtration media, the adsorbed nutrients, and the quantity of planktonic microorganisms. This exploration, combined with the concept of quality by design(QbD), aims to provide valuable insights and references for pharmaceutical manufacturers in addressing microbial control issues in pharmaceutical purified water systems.

Microneedles are a novel transdermal drug delivery method with the advantage of improving drug permeation efffciency and bioavailability. However, microneedle technology faces problems such as insufffcient hardness and poor drug delivery accuracy in actual clinical applications. Bionics is a scientific approach that constructs technical systems with specific functions by utilizing the functions and behaviors of biological systems in nature, it can effectively achieve innovative integration between systems, and provide new ideas for solving above problems. At present, bionic microneedles are widely applied in the medical field, such as assisting in wound healing, surgical operations, and physiological/pathological monitoring. This paper summarizes the researches on improving microneedle performance using bionics, and discusses the clinical development prospects of bionic microneedles to provide a new perspective for the future development of microneedle technology.

Atezolizumab, as a new PD-L1 inhibitor drug, has become one of the hot spots in tumor immunotherapy research. This review takes atezolizumab as the research object, uses patent technology analysis to study the status of related patent applications, and focuses on the patent applications of atezolizumab in China from the perspective of its technical themes and patent layout, so as to provide some effective references and suggestions for domestic research institutions and enterprises in R&D and patent layout strategies of atezolizumab.

1,2-Dipalmitoyl-sn-glycero-3-phosphorylcholine(DPPC, 1) can be used not only as a pharmaceutical excipient, but also as an exogenous lung surfactant for the treatment of neonatal respiratory distress syndrome(NRDS). Glycerophosphatidylcholine(GPC, 2) reacted with palmitic acid(PA, 3) in the presence of 4-dimethylaminopyridine (DMAP) and dicyclohexylcarbodiimide(DCC) in DCM to yield 1. But it was found that an impurity was produced, which seriously affected the puriffcation of the product. After isolation and puriffcation, the impurity was conffrmed by MS and 1 H NMR to be 1,1'-methylene-bis(4-dimethylaminopyridinium) dichloride. Through replacing reaction solvent to acetonitrile and reducing the feeding molar ratio of DMAP from 3 to 1, the yield of the target product 1 was increased from 33.20％ to 49.18％ with purity of 99.92％ .

Low-concentration atropine eyedrops, an ophthalmic formulation for delaying myopia of adolescents, has been widely recognized due to its clinical therapeutic effects. However, the commercialized atropine sulfate eyedrops, ophthalmic aqueous solution, have many problems, such as eye irritation caused by low pH value of the aqueous solution, poor stability of the preparations and poor patient compliance. In this review, the formulations and preparation processes of atropine sulfate ophthalmic preparations currently under development and on the market are summarized, the characteristics, advantages and disadvantages of various technical approaches for improving stability and compliance of atropine sulfate ophthalmic products are analyzed, hoping to provide some references for the optimization of atropine ophthalmic formulations.

In order to control the quality of cilastatin sodium(1), the synthesis of the related substances B, C and G involved in the EP 11.0, named (Z)-7-[[(2R)-2-carboxy-2-[[(1RS)-1-methyl-3-oxobutyl]amino]ethyl]- sulfanyl]-2-[[[(1S)-2,2-dimethylcyclopropyl]carbonyl]amino]hept-2-enoic acid, (Z)-7-[[(2R)-2-carboxy-2-[(1,1- dimethyl-3-oxobutyl)amino]ethyl]sulfanyl]-2-[[[(1S)-2,2-dimethylcyclopropyl]carbonyl]amino]hept-2-enoic acid and (E)-(2RS)-7-[[(2R)-2-amino-2-carboxyethyl]sulfanyl]-2-[[[(1S)-2,2-dimethylcyclopropyl]carbonyl]amino]hept-3- enoic acid, were reported in this study. Compound 1 was reacted with (E)-3-penten-2-one(2) or 4-methyl-pent-3-ene-2- one(3) via Michael addition, respectively, and purified by preparative chromatography to obtain related substances B and C. Ethyl (Z)-7-chloro-2-[[(benzyloxy)carbonyl]amino]hept-2-enoate(5) was synthesized through condensation of ethyl- 7-chloro-2-oxohept-2-enoate(4) and benzyl carbamate. The double bond of 5 was migrated by 2,2,6,6-tetramethylpiperidine lithium(LiTMP) to generate ethyl (E)-7-chloro-2-[[(benzyloxy)carbonyl]amino]hept-3-enoate(6). After deprotection of 6, followed by reaction with (S)-2,2-dimethylcyclopropane carboxylic acid(8) to obtain ethyl (E)-7-chloro-2-(S)-2,2- dimethylcyclopropane carboxamido)hept-3-enoate(9). Related substance G was obtained via the reaction of 9 and Lcysteine( 10) and the preparative chromatography. The structures of the three target products were confirmed by MS, 1H NMR and 13C NMR.

A highly sensitive LC-MS/MS method was established for detecting calcitriol content in human plasma, with a lower limit of quantification of 20 pg/mL, which could meet the clinical detection needs. A randomized, open, three cycles, triple crossover design was used to investigate and compare the pharmacokinetic characteristics and bioequivalence between the tested preparation and the commercially available reference preparation of calcitriol in 36 healthy Chinese volunteers who were given a single oral administration of calcitriol soft capsules(at a dose of 4.0 μg) on an empty stomach. The results showed that the main pharmacokinetic parameters of the tested preparation and the reference preparation were as follows: tmax were (3.46±1.33) and (2.92±1.47)h, t1/2 were (8.14±3.22) and (7.70±2.32)h, cmax were (160.68±52.41) and (169.00±50.26)pg/mL, respectively. The variance in plasma concentrations of the tested and the reference preparations showed the same trend. The geometric mean ratios of the main pharmacokinetic parameters were within the 90％ confidence interval of 80.00％ - 125.00％ , indicating that the test and reference formulations were bioequivalent.

A dye ingress method was established to assess the package integrity of prefflled syringes and vials. On the basis of setting rational parameters as well as preparing negative and positive samples, the vacuum, negative pressure holding time and the processing method of the prefflled syringe packaging system were optimized, and the method was verified. The results showed that the sensitivity of this method for assessment the integrity of the prefilled syringe packaging system and the vial packaging system was 10 - 15 μm, and was better than those in the USP, EP and International Organization for Standardization under the same conditions. This method could effectively assess the integrity of the prefilled syringe packaging system and the vial packaging system, which provided a reference for establishing the test standard for the prefflled syringe packaging system and the vial packaging system by dye ingress method.

Site-specific integration of large DNA fragments based on non-viral methods are widely used in gene therapy and cell therapy because of their low cost, large capacity, non-immunogenicity, and the ability to avoid genotoxicity and oncogene expression. According to the mechanism, non-viral methods can be classified into three types, DNA damage repair-, recombinase- and transposase-based site-specific integration technologies. All three non-viral DNA targeting methods can be combined with the clustered regularly interspaced short palindromic repeats(CRISPR) and CRISPR associated proteins 9(Cas9) technology to quickly and easily direct exogenous DNA to the target DNA region. In this study, the research progress of the three non-viral-based DNA targeting methods and their applications are summarized to provide new ideas for the development of more efficient cell therapy systems.

An HPLC method was established to simultaneously determine the contents of glycolic acid and lactic acid in leuprorelin acetate sustained-release microspheres. The Waters XSelect HSS T3 column(4.6 mm×100 mm, 3.5 μm) was used, and the analysis was carried out in the gradient elution mode with the mixed solution of phosphoric acid and water as mobile phase A, and acetonitrile as mobile phase B. The detection wavelength was 210 nm, the ffow rate was 1.0 mL/min, the column temperature was 40 ℃ , and the injection amount was 5 μL. The results showed that the method had good speciffcity, and it was linear for glycolic acid and lactic acid in the ranges of 0.015 - 0.06 mg/mL. The detection limits for both glycolic acid and lactic acid were 0.008 mg/mL, and the quantiffcation limits were 0.03 mg/mL. The average recovery rates of glycolic acid and lactic acid were 99.2 ％ and 101.6 ％ , respectively, with the RSDs were 1.54 ％ and 1.37 ％ , respectively. The results indicated that this method could be used for the determination of glycolic acid and lactic acid content in leuprorelin acetate sustained-release microspheres and their degradation process.

生物制品具有分子结构复杂、生物学活性易变和理化特性多样等特点，同时其生产工艺复杂、生产周期长，生产中 使用的各种原、辅材料亦来源多样，且制品组分一般不能耐受终端灭菌处理，导致其无菌保证方面存在特殊性。文章阐述 了无菌药品生产中微生物、热原和微粒等的污染控制策略，并重点探讨和分析了生物制品生产的无菌保证特殊性，以促进 行业提高生物制品的无菌保障能力和水平，确保生物制品安全。

The solid dispersions of a KRAS G12C covalent inhibitor, XNW14010, were prepared by fluidized-bed technology with mannitol particles as the substrates. The type and amount of the carriers and the amount of mannitol particles were optimized by the single factor experiments. The optimal formulation was using poly(vinylpyrrolidone-co-vinylacetate)( PVP-VA64) as the carriers, and the mass ratio of 1-PVP-VA64-mannitol particles was 1 ∶ 1 ∶ 1.2. By exploring and optimizing the key process parameters, the process of 1 solid dispersion was scaled up in the GMP workshop. The PXRD characterization results showed that 1 existed in an amorphous state in the solid dispersions. The SEM observation revealed that the solid dispersion particles were spherical in shape and formed an even coating layer around the mannitol substrate. Moreover, the angle of repose of the solid dispersion particles was less than 40°, making it suitable for further mixing and tableting. Based on this, a scale-up production of 1 solid dispersions-based tablets was successfully developed. In the in vitro dissolution test, the dissolution rate at 10 min of 1 from the solid dispersions-based tablets was close to 100％ in pH 6.8 PBS. An in vivo experiment was carried out with Beagle dog as a model. The results showed that the drug exposure of 1 from the solid dispersions-based tablets was 8 times higher than that of 1 tablets.

Doxorubicin is one of the potent drugs in the clinic for the treatment of blood cancers and solid tumors. However, side effects and drug resistance of doxorubicin pose major obstacles to its application in antitumor therapy. Curcumin exhibits multiple pharmacological effects such as antitumor activity, antioxidation, and anti-inflammation. When combined with doxorubicin, curcumin can enhance efficacy, reduce toxicity, and reverse multidrug resistance. Nevertheless, due to the poor solubility, instability, and low bioavailability of curcumin, the application of this combination therapy is limited. Currently, the nano drug co-delivery system offers numerous advantages in antitumor therapy. A nano-based co-loading delivery system of curcumin and doxorubicin can improve drug solubility, enhance stability, achieve targeted drug aggregation, and realize sustained- and controlled- release at the tumor site. This review summarizes the antitumor mechanisms of the concomitant use of curcumin and doxorubicin and their novel nano-based drug delivery systems in recent years, providing ideas for further research on this combination therapy and the development and application of their nano-formulations.

In order to overcome the shortcomings of sinomenine(1), such as poor water-solubility, short halflife, low oral bioavailability, the oil-in-water(O/W) 1-loaded microemulsion(1-ME) was prepared successfully by aqueous titration method via drawing pseudo-ternary phase diagrams. The prepared 1-ME with excellent stability was light yellow homogeneous and transparent with obvious Tyndall phenomenon, and the particle size was 150 ～ 180 nm, which met the particle size requirements of microemulsions. Then, 1-ME was further compounded with poloxamer(P407, P188) hydrogel to obtain the injectable 1-ME-based thermosensitive hydrogels. Furthermore, the formulation of 1-ME-based thermosensitive hydrogels was optimized with the sol-gel transition temperature(Tsol-gel) as the evaluation index. The optimized formulation was as follows: the mass ratio of P407 to P188 was 17:4, and the mass ratio of Poloxamer hydrogel to 1-ME was 8:2. The Tsol-gel of 1-ME-based thermosensitive hydrogels was(35.2±1.33)℃ , which was match to the normal physiological temperature. Finally, the in vitro release performances revealed that the cumulative release rate of 1-ME-based thermosensitive hydrogels at 48 h was (66.7±6.2)％ , which showed a satisfactory long-acting and sustained-release effect in comparison with 1-ME. In conclusion, the prepared 1-ME-based thermosensitive hydrogels was expected to be used as a novel drug delivery system of intra-articular injection for the rheumatoid arthritis treatment.

As an endogenous messenger molecule, nitric oxide has multiple effects in tumor treatment. It can not only induce tumor cell apoptosis but also achieve outstanding synergy with other treatment methods. To improve its therapeutic efficiency, researchers have designed and prepared various types of nitric oxide nanodelivery systems and applied to tumor therapy research. Among them, the controllable responsive nitric oxide nanodelivery systems have received extensive attention for their excellent on-demand release ability and brilliant therapeutic effect. This article mainly reviews the controllable responsive nitric oxide nanodelivery systems based on different nanomaterials and discusses their applications in tumor therapy from endogenous-based and exogenous-based stimuli-responsiveness respectively, in order to provide a reference for the further development of nitric oxide nanodelivery systems.

In this study, human induced pluripotent stem cells(hiPSCs) were used to construct an in vitro organoid-based substitution model for drug cardiotoxicity. The hiPSCs were cultured to determine the optimal differentiation generation, and pluripotency was identified using immunofluorescence staining. The hiPSCs were seeded into ultra-low adsorption 96-well plates at different cell densities, and the medium containing growth factors and signaling pathway inhibitors were added for inducing differentiation, and the morphological changes and pulsatile characteristics were recorded by light microscopy. Cardiac organoids at different time points in the differentiation process were collected, and real-time reverse transcription-quantitative polymerase chain reaction(RT-qPCR) was adopted to detect the relative expression of cell-specific genes of cardiac organoids. The results showed that the resuscitated hiPSCs grew well with clear edges and excellent cell pluripotency. The morphology of the differentiated cardiac organoids at a density of 5 000 cells per well was the best, and trended to be a relatively stable state for 8 - 10 d culturing, and a relatively stable state could be maintained within 18 d. RT-qPCR results showed that specific genes of cardiomyocytes and other cardiac components, such as endothelial cells, smooth muscle cells, and fibroblasts, were expressed. The establishment of cardiac organoid models in this study can more realistically and accurately simulate the biological characteristics and functions of the heart in vivo, which lays a foundation for the subsequent use of cardiac organoid models for potential cardiotoxicity studies of drugs in the early stage of research and development.

Finerenone(1) was synthesized from diketene and 4-methoxybenzylamine as the starting materials, through the aminolysis, condensation, Hantzsch cyclization, ethylation, and chiral resolution steps. After optimizing the reaction conditions, the overall yield of this process was 11.4％ with the purity of 99.7％ . The usage of 4-methoxybenzyl group as the protection group was reported at the first time in this route, which was suitable for industrial production.

Using fluorene(2) as the starting material, it was chlorinated by trichloroisocyanuric acid to obtain 2,7-dichlorofluorene(3), which was acylated with chloroacetyl chloride to produce 2,7-dichlorofluorene-4-chloroethyl ketone(4). Then, α-(di-n-butylaminomethyl)-2,7-dichloro-4-fluorenylmethanol(5) was obtained via reduction, cyclization and amination by one-pot method. Finally, 5 was condensed with p-chlorobenzaldehyde to obtain benfluorenol(1), with an overall yield of 36％ and a purity of 99.4％ . The improved process used trichloroisocyanuric acid as the chlorinating agent, which improved the selectivity and safety of the reaction. The reduction, cyclization and amination were completed by onepot method, which reduced the reaction temperature, shortened the reaction cycle, improved production efficiency, and increased the yield from 60％ to 80％ . The improved process was simple to operate, low in production cost and suitable for industrial production.

This study prepared three impurities of alprazolam(1) namely impurities D, H, and J, which were recorded in the EP10.0, but their synthetic routes had not been reported in the literature. Additionally, during the stability study of 1 bulk drug, a new impurity Q was discovered. Its chemical structure was determined as [5-chloro-2-[3-[[[(7- chloro-5-hydroxy-5-phenyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-1-yl)methyl]amino]methyl]-5-methyl-4H-1,2,4- triazol-4-yl]phenyl](phenyl)methanone through high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy. The successful preparation of these four impurities is of great significance for the quality research of 1 bulk drug and its formulations.

Self-microemulsifying drug delivery system(SMEDDS) is one of the effective approaches to improve the solubility and bioavailability of poorly soluble drugs. The formulation screening and optimization is the key steps in the development of SMEDDS products. Design of experiment(DoE) methods are employed to evaluate the main effects of independent variables and their interactions on response variables in formulations, therefore they are widely used in formulation optimization. This review summarizes the principles, advantages and disadvantages of several experimental design methods and their application in SMEDDS products development, focusing on the D-optimal mixtures design, in order to provide some references for the selection of SMEDDS formulation optimization methods.

FDA 正式批准了2 款人用新型冠状病毒感染(COVID-19)mRNA 疫苗药物，分别为莫德纳(Moderna) 公司的 Spikevax，以及辉瑞/BioNtech 的Comirnaty，可作为该类技术里程碑意义的案例进行监管分析。COVID-19 mRNA 疫苗已 在国内紧急授权使用，但尚未正式获批上市，因此针对该类疫苗药物研发及监管的指导资料有限。文章基于FDA 公开的审 评资料，结合国内对疫苗的监管要求，对照解析mRNA 疫苗的审评特点，总结监管关注点，以期为我国mRNA 疫苗的发 展提供一定参考。

The paddle apparatus is commonly used in both research and development(R&D) and quality control. However, because the settling position of the product after falling into the dissolution vessel may change the diffusion range of drug disintegration at the bottom of the vessel, it is often affected by the problems of reproducibility and accuracy, which may not reflect the drug release characteristics precisely. To achieve better reproducibility, the new modified paddle apparatus was improved by adding auxiliary beads at the bottom of the glass vessel of the paddle apparatus. In addition, the size of the auxiliary beads can be selected according to the dissolution behaviors of different drugs. In this study, entacapone(1) tablets, dapagliflozin(2) tablets and clarithromycin(3) tablets were used as model drugs to Investigate the effects of the improved paddle apparatus, traditional vessel and apex vessel. The results indicated that the improved paddle dissolution vessel could not only select the corresponding auxiliary beads more flexibly according to the drugs, but also obtain better reproducibility of the drug release curves, which was beneficial to the comparison of dissolution results between batches or laboratories.

Deuterium substitution is a method that involves replacing specific hydrogen(H) atoms in drug molecules with deuterium(D) atoms, thereby improving the absorption, distribution, metabolism, and affecting of the drug molecules within the body. It can reduce the dosage or frequency of administration, enhance safety, and achieve better therapeutic outcomes. Nowadays, deuterium substitution has become an important strategy in rational drug design and optimization of druggability. The methods of deuterated modification primarily include chemical synthesis and enzymatic catalysis. Chemical synthesis encompasses techniques such as the introduction of deuterated intermediates, halogen or unsaturated bond reduction, acid/base catalysis, and metal-catalyzed hydrogen-deuterium exchange. Enzymatic catalysis involves methods such as enzyme-catalyzed hydrogen-deuterium exchange, reductive deuteration, and decarboxylative deuteration. This review outlines the latest research progress of drug molecule deuteration in recent years with the aim of providing references for the research and development of deuterated drugs.

Four potential related substances were synthesized, namely 2-[(7R,11R)-2,3-dihydroxy-3,7,11,15- tetramethylhexadecyl]-3-methylnaphthalene-1,4-dione(related substance A), 1α-methyl-7α-[(7R,11R,E)-3,7,11,15- tetramethylhexadec-2-en-1-yl]-1α,7α-dihydronaphtho[2,3-b]oxirene-2,7-dione(related substance B), 2-[(7R,11R,E)-3- hydroxy-3,7,11,15-tetramethylhexadec-1-en-1-yl]-3-methylnaphthalene-1,4-dione(related substance C) and 2,5-dimethyl- 2-[(4R,8R)-4,8,12-trimethyltridecyl]-2H-benzo[h]chromen-6-ol(related substance D).Their structures were confirmed by 1H NMR and MS, which provided a reference for the quality control of vitamin K1.