Chinese Journal of Pharmaceuticals

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Perspectives & Review

Challenges and New Developments of Oral Peptide Delivery

RUAN Sida, FENG Jun, LI Yanan, DONG Yuanzhen, LU Weigen

2020, 51(12): 1475-1486. https://doi.org/10.16522/j.cnki.cjph.2020.12.001

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Achieving oral delivery of peptide drugs has drawn a lot of attention in recent years. However, the complex gastrointestinal barriers cause extremely low oral bioavailability. In this review, we summarize the important barriers to oral absorption of peptide drugs as well as different strategies for overcoming the corresponding barriers. At the same time, new technologies and advances in oral delivery of peptide drugs are also presented in this paper, which will bring new hope for improvement in oral bioavailability of peptides.

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Perspectives & Review

Progress in the Formulation of Approved Nucleic Acid Drugs

CHEN Wenfei, WU Fuhua, ZHANG Zhirong, SUN Xun

2020, 51(12): 1487-1496. https://doi.org/10.16522/j.cnki.cjph.2020.12.002

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In recent years, due to the enhanced knowledge about the genetic basis of disease, nucleic acid drugs including plasmid DNA, antisense oligonucleotide, small interfering RNA, microRNA, and other gene-based therapies have drawn wide attention on a global scale, and some of these nucleic acid drugs have been approved for clinical use. However, a series of systemic and intracellular obstacles for gene delivery, such as fast degradation in blood, rapid hepatic and renal clearance, low cellular uptake efficiency, and inefficient endosomal escape, have greatly hindered the development of nucleic acid drugs. Therefore, viral and non-viral gene delivery systems become the major technological means to transport genes to reach cytosol or cell nucleus, and to achieve therapeutic effect. In this review, we introduce the barriers and challenges of gene delivery in vivo, summarize recent advances on the approved nucleic acid drugs, and mainly discuss their delivery systems from the aspects of formulations.

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Perspectives & Review

Advances in Inhalable siRNA Delivery Systems

ZHOU Yong, ZHAO Di, YANG Lei, YIN Lifang

2020, 51(12): 1497-1508. https://doi.org/10.16522/j.cnki.cjph.2020.12.003

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The extensive siRNA related researches have been carried out in the fields of various diseases' treatment as the lower toxicity and specific target genes silencing of siRNA. However, due to the poor stability of siRNA in vivo and the lack of appropriate delivery vehicles, there are still many challenges in delivering siRNA precisely. Inhalation can directly deliver drugs to the lungs, and exhibits an excellent therapeutic effect on respiratory tract and lung diseases. Thus, it is critical to develop suitable vehicles of siRNA for inhalation delivery to overcome the existing biological barriers and intracellular barriers. Many studies have been carried out in inhalable siRNA delivery systems, and great progress has been achieved in the treatment of pneumonia, cystic fibrosis and chronic obstructive pulmonary disease. Based on the commonly used inhalable siRNA delivery systems, this paper reviews the components of each delivery vehicle, analyzes the advantages and disadvantages of diverse delivery systems, and summarizes the future development trend of inhalable siRNA delivery systems in detail.

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Perspectives & Review

An Overview of Drug Delivery Systems Based on Polymer-drug Conjugates

MENG Qingqing, LUO Jing, WANG Hao

2020, 51(12): 1509-1516. https://doi.org/10.16522/j.cnki.cjph.2020.12.004

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Perspectives & Review

An Overview of Factors Affecting in vivo and in vitro Release of Long-acting Injection of Nanocrystal Suspensions

DING Jingwen, WANG Junji, HE Jun

2020, 51(12): 1517-1528. https://doi.org/10.16522/j.cnki.cjph.2020.12.005

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In recent years, long-acting injection of nanocrystal suspensions(LAI-NS) has become a research hotspot due to its advantages in the treatment of chronic diseases[such as mental illness and human immunodeficiency virus(HIV) infection]. This paper reviews the factors affecting the in vitro and in vivo release of LAI-NS, introduces the evaluation methods for in vitro release and in vivo-in vitro correlation(IVIVC). The influence factors on drug-loaded particles entering systemic circulation during local tissue inflammation process and the advances in application of local tissue imaging technology in quality evaluation of LAI-NS are briefly introduced. It is expected that this paper can provide some references for establishing IVIVC models and quality evaluation system of LAI-NS.

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Perspectives & Review

Research Progress on Effect and Mechanism of Bile Salts in Promoting Oral Absorption of Drugs

CAI Yifan, ZHANG Zichen, LU Yi, QI Jianping, WU Wei

2020, 51(12): 1529-1540. https://doi.org/10.16522/j.cnki.cjph.2020.12.006

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Bile salts are physiological surfactants with a steroidal core, which can increase the solubility of lipophilic drugs in the form of mixed micelles, assisting polar drugs to overcome intestinal epithelial barrier, thus improving the oral bioavailability of drugs with poor solubility and permeability. Recently, preparations containing bile salts have received widespread attention in the field of oral drug delivery. Phospholipid/bile salt mixed micelles, bilosomes, bile salt modified nanoparticles, drug-bile salt conjugates are all promising drug delivery systems. We review the effect and mechanism of bile salts and their preparations in promoting oral absorption of drugs, as well as the preparation methods of bile salt drug delivery systems. The advantages and disadvantages of these delivery systems are discussed in order to provide some references for the development of bile salt preparations with high oral bioavailability.

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Paper

Selection of Dissolution Conditions of Four Active Lactones in Chuanxinlian Tablets Based on in vitro and in vivo Correlation

LI Kun, WANG Qizheng, CHEN Jun, ZUO Zhong, ZHANG Rong, WANG Qi, WANG Jianxin

2020, 51(12): 1541-1548. https://doi.org/10.16522/j.cnki.cjph.2020.12.007

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In order to establish an in vitro dissolution method with good correlation with in vivo absorption of active lactones in Chuanxinlian tablets, the dissolution profiles and pharmacokinetics in Beagle dogs of andrographolide, neoandrographolide, 14-deoxyandrographolide, and 14-deoxy-11,12-didehydroandrographolide were measured. A high-performance liquid chromatography was employed to determine the dissolution rates of above four lactones from Chuanxinlian tablets in different dissolution media(pH 1.0 HCl, pH 4.5 acetate buffer, pH 6.8 phosphate buffer and water) at different rotation speeds(50, 75 and 100 r/min). The plasma concentrations of four lactones in Beagle dogs after oral administration of Chuanxinlian tablets at different time intervals were analyzed with LC-MS/MS and the plasma concentration-time curves were plotted. Phoenix software was used to fit the models of in vitro dissolution and in vivo absorption fractions of four lactones in Chuanxinlian tablets. The correlation between dissolution rates and absorption fractions was established. The results indicated that there was a good correlation between the absorption rates and dissolution profiles when using pH 4.5 acetate buffer as medium and rotating at 100 r/min. It can be concluded that the dissolution in pH 4.5 acetate buffer at 100 r/min is suitable for the quality control of Chuanxinlian tablets.

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Identification and Control of Critical Quality Attributes of Carboxymethylcellulose Sodium in Mesalazine Sustained-release Tablets

ZHANG Xiaona, WANG Jue, SUN Kaoxiang, SUN Huimin

2020, 51(12): 1549-1557. https://doi.org/10.16522/j.cnki.cjph.2020.12.008

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In this paper, various physical parameters of carboxymethylcellulose sodium(CMC-Na) from four different manufacturers were investigated, and the mesalazine sustained-release tablets with CMC-Na from different manufacturers were prepared. The release similarity between the self-made sustained-release tablets and reference listed drug(RLD) were also evaluated by the similarity factor(f2) method. Then, orthogonal partial least squares(OPLS) was adopted to establish a correlation model between physical parameters of CMC-Na and f2 values. Thereby, the potential critical quality attributes(CQAs) for CMC-Na were screened by multivariate statistical modeling with variable importance in the projection(VIP) as the index. According to the results, the bulk density, weight-average molecular weight, tap density and specific surface area were identified as the CQAs for CMC-Na in mesalazine sustained-release tablets. Then, the response surface plots of f2 values versus above four CQAs were drawn to find the design space. The results showed that the f2 value between RLD and the self-made sustained-release tablets containing CMC-Na with bulk density>0.517 32 g/cm3, weight-average molecular weight>644 710 g/mol, tap density>0.793 87 g/cm3 and specific surface area>0.659 m2/g reached 50, indicating their release consistency in vitro. This study provides a basis for future research and development of generic drugs. The drug development process would be more clear and controllable.

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Investigation on the Release Similarity of Low-dose Conjugated Estrogens Sustained-release Tablets between Generic Preparation and Reference Listed Drug

LI Xinrong, LIANG Liwei, SHAN Yu, YIMITI Adilijiang, LIU Xiaohang, GAO Xiaoli

2020, 51(12): 1558-1563. https://doi.org/10.16522/j.cnki.cjph.2020.12.009

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Influences of Coating Parameters on Transparency of Semi-permeable Membrane Coating on Push-pull Osmotic Pump Tablets

YANG Jirong, CHEN Wei, ZHU Ying

2020, 51(12): 1564-1569. https://doi.org/10.16522/j.cnki.cjph.2020.12.010

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The transparency of the semi-permeable membrane coating on the push-pull osmotic pump tablets is very important for the identification of the drug layer and the push layer in laser drilling machine. In the process of semipermeable film coating, the phenomenon of whitening of semi-permeable membrane occurs from time to time. In this paper, the push-pull osmotic pump tablets coated with cellulose acetate as semi-permeable membrane with the brownish red tablet cores were prepared, and color difference analysis was adopted to evaluate the transparency of the semipermeable membrane with delta E(DE) value as a quantitative indicator. The JMP 10.0 statistic software was used to carry out the random customized experimental design for 12 experiments, including one central point. The influences of the selected coating process parameters including inlet airflow volume, inlet temperature, liquid spraying rate, coating weight gain and relative humidity of actual environment on transparency of the semi-permeable membrane were investigated. The results showed that the influences of liquid spraying rate, inlet temperature and their interaction significantly influenced transparency of the semi-permeable membrane, and bed temperature and its interaction with relative humidity of actual environment were also significant factors leading to film opacity.

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Paper

Design and Evaluation of MCT1-targeting Cytarabine Prodrug for Enhanced Oral Delivery

QIN Liuxin, CHEN Weiwei, WANG Gang, ZHAO Lichun, WANG Yang

2020, 51(12): 1570-1577. https://doi.org/10.16522/j.cnki.cjph.2020.12.011

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Intestinal mono-carboxylate transporter 1 (MCT1) distributes throughout the intestine and plays an important role in the oral absorption of short-chain fatty acids, thus being considered as a potential target for prodrug design. Cytarabine is a first line antineoplastic drug for treating malignant lymphoma and acute leukemia. However, the poor membrane permeability and stability limit its oral bioavailability. Therefore, the intestinal MCT1 targeted prodrug was designed to improve the oral bioavailability of cytarabine using succinic acid as ligand. Due to the good stability of amide bond, the half-life of prodrug was over 10 h in pH 1.2 and 6.8 phosphate buffer solutions, while it rapidly degraded to release parent drug in pH 7.4 phosphate buffer solution, plasma and tissue homogenates. The results of in vitro cellular uptake test suggested that the prodrug was absorbed into Caco-2 cells by the H+ and temperature dependent, and MCT1 mediated mechanism. And the membrane permeability of the prodrug was 9 times higher than that of the parent drug. In pharmacokinetic test of rats, tmax of the prodrug was about 1.1 h, indicating the rapid absorption after oral administration. And the oral bioavailability of the prodrug was 32.1％, which was 3 times higher than cytarabine. Above all, intestinal MCT1 can be used as an ideal target to design oral prodrug.

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Effects of Loading and Particle Size of Magnesium Hydroxide on in vitro Drug Release Behavior of Exenatide-loaded PLGA Microspheres

QI Menglin, WANG Meng, CHEN Jili, WU Fei, JIN Tuo

2020, 51(12): 1578-1585. https://doi.org/10.16522/j.cnki.cjph.2020.12.012

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The long-acting microspheres with exenatide as model drug were prepared by solid-in-oil-in-water emulsion-solvent evaporation method with poly(lactic-co-glycolic acid)(PLGA) as a carrier and magnesium hydroxide as an antacid. Through adding different amounts of magnesium hydroxide with different particle sizes, the effect of magnesium hydroxide on sustained-release behavior of exenatide from the microspheres was investigated. In vitro release process of the prepared microspheres was characterized by scanning electron microscopy, particle size distribution, loading levels of exenatide and magnesium hydroxide, cumulative drug release and pH change of release medium. In vitro release test showed that the loading level of magnesium hydroxide had a significant effect on prolongation of drug release. With the increasing of magnesium hydroxide loading level, the degradation degree of PLGA was inhibited and the processes of microspheres erosion, shrinkage, collapse and rupture were also delayed. It had a guiding significance in development of long-acting microspheres. No obvious effects of particle size of magnesium hydroxide on release behavior of the microspheres were observed. Therefore, antacid magnesium hydroxide described in this study has a good application potential in development of long-acting microspheres.

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Policy & Regulation

Evolution and Analysis of Revision of General Chapters for Injection in Chinese Pharmacopoeia

LIN Xiujun, GAO Xie, ZHOU Jianping, DING Yang

2020, 51(12): 1586-1593. https://doi.org/10.16522/j.cnki.cjph.2020.12.013

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Policy & Regulation

Current Status and Trend of Chinese Chemical Generic Drugs for Global Registration

JIANG Hui, WANG Lijie, GUO Xiaodi