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.

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.

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.

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.

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.

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.

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).

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.

The main metabolites of linezolid, PNU-142300(2) and PNU-142586(3), were synthesized. Compound 3,4-difluoronitrobenzene(5) was used as the starting material to synthesize the key intermediate (S)-2-[[3-[4-[benzyl[2- [(tert-butyldimethylsilyl)oxy]ethyl]amino]-3-fluorophenyl]-2-oxooxazolidin-5-yl]methyl]isoindoline-1,3-dione(15) by nucleophilic substitution, hydroxyl protection, nitro-reduction reaction, condensation and cyclization. Metabolite (S)-2-[2-[[4-[5-(acetamidomethyl)-2-oxooxazolidin-3-yl]-2-fluorophenyl]amino]ethoxy]acetic acid(namely PNU- 142300) was obtained from 15 by removal of tert-butyldimethylsilyl(TBS) group, Williamson etherification, amolysis, acylation, debenzylation and removal of tert-butyl group in sequence with total yield of 78％ and the purity of 98.62％ . Metabolite (S)-N-[4-[5-(acetamidomethyl)-2-oxooxazolidin-3-yl]-2-fluorophenyl]-N-(2-hydroxyethyl)glycinate (namely PNU-142586) tetrabutylammonium salt was obtained from 15 by amolysis, acylation, debenzylation, nitroalkylation, debenzylation and TBS removal in sequence with total yield of 65％ and the purity of 92.35％ . The structures of 2 and 3 were confirmed by MS, 1H NMR and 13C NMR.

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.

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.

The acid water extraction method was designed, and a new refining process for the sinomenine extraction solution was developed. Experimental parameters for extraction and purification were determined by computational optimization, and experimental verification was performed. Chloroform was recycled for 10 times. The content of sinomenine hydrochloride in the prepared product was determined by HPLC. The experimental parameter ranges were set as follows: in the alkaline system(E1), the pH value ranged from 9 to 10. During the extraction process, the volume ratio of chloroform to E1 was 1 ∶ 10. During the water-washing process, the volume ratio of organic phase(O1) to water was 1 ∶ 3. During the acid-water stripping process, the volume ratio of organic phase(O2) to water was 1 ∶ 8. In the aqueous phase(A1), the pH value ranged from 4 to 5. Under the same feed amount, after chloroform was reused for five times, the purity of prepared sinomenine hydrochloride maintained stable. This study developed a new process for the preparation of sinomenine hydrochloride, demonstrating the feasibility of recycling chloroform and obtaining high-purity sinomenine hydrochloride, which could reduce solid waste and production costs.

Based on the quality by design(QbD) concept and subcritical water extraction technology, the preparation process of Bupleurum chinense granules was optimized, and the physical quality consistency of different batches of Bupleurum chinense granules was evaluated using the physical fingerprint method. The Box-Behnken designresponse surface method was adopted to optimize the subcritical hot water extraction technology. Multi-index comprehensive weighting method was used to determine the process parameters of molding. The physical fingerprint of granules was established with repose angle, Hausner ratio, moisture, hygroscopicity, relative homogeneity index, bulk density and tap density as the indexes. The optimized process parameters of Bupleurum chinense guanules were determined to be a solid-liquid ratio of 1 ∶ 14, extraction time of 40 min, and extraction temperature of 131 ℃ . The final granules were prepared by wet granulation with microcrystalline cellulose as the filler, a drug to auxiliary ratio of 1 ∶ 1, and 90％ ethanol as the humectant. The physical fingerprint similarity of different batches of the granules was higher than 0.99. The results indicated that the optimized preparation process of Bupleurum chinense guanules was stable and feasible, with high extraction efficiency, and the physical quality of the prepared granules was stable, which could provide new ideas for the research and development of traditional Chinese medicine preparations.

A microwave digestion-inductively coupled plasma mass spectrometry(ICP-MS) method was established for the simultaneous determination of twenty-four elemental impurities in sodium oleate. The results showed that it was linear for twenty-four elemental impurities in the corresponding mass concentration ranges(r>0.997 0). The average recoveries(n=9) were 87.04％ - 114.7％ , with the RSDs of less than 9.8％ . The eighteen batches of sodium oleate samples from four manufacturers were tested, and the Ni element contents in three batches of samples from one manufacturer were close to or exceed its control threshold, while the remaining twenty-three elements were far below the control threshold. The established method has high sensitivity and good accuracy, which can be used for trace control of twenty-four elemental impurities in sodium oleate.

Using recovery rate and precision as evaluation indicators, the feasibility of methyl esterification gas chromatography, non-derivatization gas chromatography, and HPLC method with charged aerosol detector(CAD) for determining the migration of lubricants in carboxylic acid drugs was investigated. The results showed that compared with the methyl esterification gas chromatography and the non-derivatization gas chromatography, the HPLC-CAD method had higher recovery rate and precision. The recovery rate, precision, and detection limit of lubricant palmitic acid by the HPLC-CAD method were 103.5％ - 107.8％ , 1.6％ , and 1.01 μg/mL, respectively. Then, the recovery rate, precision, and detection limit of lubricant stearic acid were 100.9％ - 109.3％ , 1.4％ , and 1.00 μg/mL, respectively. The valproic acid injection after accelerated storage for 0 and 3 months was detected by HPLC-CAD method, and no migration of lubricant palmitic acid and stearic acid was found from halogenated butyl rubber stoppers to the solution. The HPLC-CAD method established in this paper can be used to detect the migration of lubricants from halogenated butyl rubber stoppers to carboxylic acid drugs.