In this study, the synthetic method of sparsentan(1) was improved. With 4-bromo-3-methylbenzonitrile(2) as the starting material, 3-(ethoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(6) was obtained via free radical substitution, nucleophilic substitution, cyano reduction, Miyaura borylation. In another way, the condensation of 2-bromobenzenesulfonyl chloride(7) with 3-amino-4,5-dimethylisoxazole(8) was conducted, followed by the amino-protection to give 2-bromo-N-(4,5-dimethylisoxazol-3-yl)-N-[(2-methoxyethoxy)methyl]benzenesulfonamide(11). Intermediates 6 and 11 reacted via Suzuki coupling reaction to get N-(4,5-dimethylisoxazol-3-yl)-2'- (ethoxymethyl)-4'-formyl-N-[(2-methoxyethoxy)methyl]-[1,1'-biphenyl]-2-sulfonamide(12), then the target compound 1 was obtained from compound 12 via reduction, bromination, condensation and deprotection. The total yield was about 43.25％ (based on 2) with the purity of 99.5％ . The optimized route avoided the usage of the dangerous and toxic reagents such as n-butyl lithium and carbon tetrabromoide, and simpliffed some puriffcations.

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.

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).

Amorphous solid dispersion is one of the most effective formulation approaches to enhance the oral bioavailability of poorly water-soluble drugs with wide application prospects. However, due to the “aging”, a solid state physical stability problem, which affects the dissolution in vitro and absorption in vivo, the development of amorphous solid dispersion-based preparations faces great challenges. The solid state physical stability is affected by many factors such as formulation composition, preparation process and storage conditions. In this paper, formulation composition, preparation process and quality control of amorphous solid dispersion-based preparations are summarized in order to provide the guidance for the development of amorphous solid dispersion-based preparations.

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.

Lemborexant(1) is an orexin receptor antagonist drug used for the treatment of insomnia. The chemical structure of this drug is relatively complex, with two chiral centers and a cyclopropane structure, which creates certain difficulties for chemical synthesis. This review analyzes and summarizes the synthesis routes of 1 from the perspective of how to construct chiral cyclopropane, using 3-fluorophenylacetonitrile(5), 2-bromo-5-fluorophenylacetic acid(20), allyl 2-(3-fluorophenyl)acetate(23) or methyl 3-fluorophenyl acetate(30) as the starting materials, with corresponding mechanism analysis in the key part and a brief overview of each route.

In view of the discovery of nitrosamine impurities in angiotensin Ⅱ receptor antagonists, histamine 2 receptor antagonists, antimicrobial drugs, antidiabetic drugs and other drugs, global regulatory agencies have signiffcantly increased their supervision on nitrosamine impurities. Regulatory agencies in various countries have successively issued the corresponding guiding documents, developed risk assessment methods, and proposed control strategies for nitrosamine impurities in drugs. China has also successively introduced a series of guiding documents that are in line with the international standards to control nitrosamine impurities. However, in practical work, there are still difficulties in the generation pathways, risk assessment, and control strategies for nitrosamine impurities. This article mainly introduces the possible nitrosation pathways and formation causes of nitrosamine impurities in chemical drugs, as well as the overall requirements for the analysis methods. And the risk assessment and control strategies for nitrosamine impurities in chemical drugs proposed by the regulatory agencies in various countries are summarized, which can provide a reference for further research and control of nitrosamine impurities.

Microfluidic chips have been widely used in drug delivery, real-time detection, cell sorting and organ chips. Based on the application of microfluidic chips in skin-related research fields, this review mainly introduces the basic principles of microfluidic flow in microfluidic chips, the manufacturing materials and compositions of chips, and the application of microfluidic chips in the development of drug transdermal delivery systems, percutaneous detection and modeling of skin diseases. It is hoped that this review can provide references for researchers in the preparation of transdermal drug delivery systems, health monitoring and looking for in vitro skin model.

Oral administration is by far the most commonly used route of drug administration. Through the rational design and optimization of oral formulations and their preparation processes, increase of solubility, sustained- and controlled-release of drugs can be achieved, resulting in improved oral bioavailability, enhanced efffcacy, reduced toxicity or personalized drug delivery. However, the current formulation and preparation process optimization of oral formulations is still highly dependent on traditional trial-and-error experiments and empirical data, which is time-consuming, laborious, costly, and hardly predictable. Artiffcial intelligence(AI) technology, which has ffourished in recent years, is expected to enable efffcient and systematic design of oral formulations. Based on the existing experimental data for oral preparations, a prediction model can be established through AI to predict the relevant indicators of oral preparations and optimize the process parameters of oral preparations. This review summarizes the basic principles and applications of AI-assisted development in oral formulations, discusses and offers prospects on the applications of AI in the ffeld of oral formulations, and provides a reference for accelerating further research and development of pharmaceutical preparations with AI technology.

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.

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。

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.

Ultrasound imaging has been widely used in various fields due to its non-invasiveness, relative simplicity, and no ionizing radiation. Ultrasound contrast agents play an important role in ultrasound imaging, which are usually composed of soft or hard shell materials, with sizes ranging from nanometers to micrometers. And their functions have evolved from initial imaging diagnosis to the integrated mode of diagnosis and treatment. Some marketed ultrasound contrast agents, such as Levovist®, Optison®, Definity® and SonoVue® have been used in clinical ultrasound examinations in Europe, Asia and elsewhere. This review focuses on the research progress of microbubble ultrasound contrast agents and their clinical applications, in order to provide a reference for the development of new ultrasound contrast agents.

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.

Proteolysis targeting chimeras(PROTACs) are currently one of the hot spots in antineoplastic agent research. They have efffcient and durable anti-tumor effects, good selectivity, and low possible toxicity. This review summarizes the research progress of new PROTAC drugs targeting estrogen receptors, androgen receptors, BCR-ABL, histone deacetylase 4, methyltransferase-like 3.

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.

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.

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.

欧美围绕细胞和基因治疗产品全生命周期已建立了较为完善的监管体系。文章采用文献研究法、比较研究法，搜集、 整理欧美及我国细胞和基因治疗产品的监管策略，分析关键点，并进行详细比较和梳理。我国在顶层立法、全生命周期技 术指导原则覆盖范围、监管机构设置及监管模式等方面仍相对薄弱，建议国家在以“患者为中心”的原则上，对细胞和基 因治疗产品构建集法律法规、指导原则等为一体的监管体系，设立专业咨询/ 评审机构，激励特定疾病的产品研发，并进 一步探索基于产品风险实施差异化管理。

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。

In recent years, organoids and organ chips have been developed rapidly. Organoids show certain advantages such as physiological, human origin, genetic stability, high throughput and easy operation, and can be widely used in many fields including drug development, drug evaluation and regenerative medicine. The application of organoids to drug developing include the evaluation of pharmacodynamics, pharmacokinetics, effectiveness and safety, especially for non-clinical pharmacodynamic evaluation. Here, the applications of organoids and their representative models in drug evaluation are introduced, the regulatory international regulatory policy and industry developments are briefly reviewed. Finally, the applications and challenges of organoids and organ chips for non-clinical alternative or complementary models are discussed.

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.

Investigating the impacts of reciprocating frequency and screen aperture on the dissolution behavior of aspirin enteric-coated tablets. Establishing a reciprocating cylinder method for determining the dissolution of aspirin enteric coated tablets, to figure out the in vitro dissolution profiles for different formulations. The dissolution behavior of reference listed drugs and 4 test formulations was evaluated by f2-bootstrap method, the similarity factor(f2) of the dissolution profiles between formulations A, B, C, D and reference listed drugs was 81.4, 33.5, 20.9 and 17.9. The dissolution profiles of formulation A and reference listed drugs were similar, however, the dissolution profiles of formulation B, C and D were different. Compared with basket apparatus, using reciprocating cylinder is a discriminative and durable method for dissolution behavior characterization of aspirin enteric-coated tablets, providing reference for the application of reciprocating cylinder method in drug quality evaluation.

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.

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.

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％ .

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.

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.

根据2022 版欧盟GMP 附录1 关于洁净室监测的要求，探讨洁净室污染控制策略的有效性和科学性。该文运用网 格化风险评估工具，将洁净区域划分为高、中、低风险区，结合颗粒物与微生物的监测指标，比较网格化与未网格化划分 所得的监测数据结果，尝试建立稳定且实用的洁净室环境监测计划。结果显示，网格化划分后的各项监测数据结果均符合 可接受标准。相较于未进行网格化划分的监测方法，该方法能探索洁净室环境的“最差情况”。洁净环境监控的侧重点已 经从单独要素控制转向整体策略控制，应关注关键区的气流流型、建立整体性的污染控制策略，以保证洁净环境符合欧盟 GMP 附录1 的要求。

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.

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。

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。

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.

The current majority therapeutic approaches for esophageal diseases are systemic administrations, which often present disadvantages such as limited efficacy and significant adverse effects. Local administration can efficiently increase the concentration of drugs at the lesion sites, making it particularly suitable for the treatment of esophagitis, esophageal cancers, and other esophageal diseases. However, esophageal administration still faces numerous difficulties, the most significant of which are the short drug retention time and the difficulty of penetrating the mucosa. In recent years, various new delivery systems have been developed for localized esophageal drug delivery to overcome the challenges posed by esophageal histology and physiology, offering new hope for patients with related diseases. Based on the introduction of the histological and physiological features of the esophagus, this review analyzes the challenges of local drug therapy, summarizes the new progress in drug administration schemes like oral preparations, esophageal stents and local injections as well as the development of in vitro and in vivo evaluation methods, which provide some references for the further development of esophageal local drug delivery systems.

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.

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 order to control the quality of crisaborole(1) and its tablets, six related substances were synthesized based on the synthetic process of 1, namely 3-(4-cyanophenoxy)benzyl acetate(related substance A), 4,4'-di(4- cyanophenoxy)-2,2'-bis(acetoxymethyl)biphenyl(related substance B), 4,4'-di(4-cyanophenoxy)-2,2'-bis(hydroxymethyl)- biphenyl(related substance C), 4-[4-[4-bromo-3-(hydroxymethyl)phenoxy]-3-(hydroxymethyl)phenoxy]benzonitrile (related substance D), 5-[2-(acetoxymethyl)-4-(4-cyanophenoxy)phenoxy]-2-bromobenzyl acetate(related substance E) and 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-5-yl)oxy]benzoic acid(related substance F). Their structures were conffrmed by 1 H NMR, 13 C NMR and MS, and the purities of all impurities were greater than 97％ .