Chinese Journal of Pharmaceuticals

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Perspectives & Review

Survey Research of Influence Factors and Evaluation Methods for Glass-forming Ability of Drugs

OUYANG Liaoqi, ZHAO Guowei, JIANG Qieying, ZENG Huiling, LIAO Zhenggen

2022, 53(02): 167-174. https://doi.org/10.16522/j.cnki.cjph.2022.02.001

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At present, many active pharmaceutical ingredients have not been developed in formulations due to their low aqueous solubilities, which cause low bioavailabilities of drugs. Therefore, improving the solubility and bioavailability of drugs is an important challenge in preparation research. The transformation of drugs from crystalline state to amorphous state can greatly increase the solubility, resulting in higher dissolution rate and bioavailability. Understanding and mastering the glass-forming ability(GFA) of drugs(namely the transformation ability of a crystalline compound to an amorphous state) and their influence factors are the basis for judging the suitability of preparation of amorphous drugs. Therefore, this review analyzes the influence factors of GFA from the aspects of drug structure, thermodynamic properties, kinetic properties and external environment. The methods to evaluate GFA of drugs are also summarized. It is hoped to provide a reference for the development and design of amorphous preparations.

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Perspectives & Review

Advances in Orally Inhaled Drug Products

LU Chenghao, LIU Ali, WANG Qingjuan, FENG Zhong, ZHANG Guimin

2022, 53(02): 175-183. https://doi.org/10.16522/j.cnki.cjph.2022.02.002

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Orally inhaled drug products are a combination of aerosol generating devices with different principles and corresponding drug forms. It is the first-choice therapy for prevention and treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease(COPD). Orally inhaled drug products not only have technical challenges in the formulation development, but also have many difficulties in their use. This study summarizes the recent research progress of orally inhaled drug products in improving patient compliance, overcoming delivery dose limitations, improving atomization by controlling particle characteristics, and expanding the scope of treatment, as well as the development of relevant regulations and guidelines. The innovations in process, formulation, device, standard and treatment field are reviewed, hoping to provide some references for researches on orally inhaled products.

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Perspectives & Review

Research Progress in Determination Methods and Applications of Shikimic Acid in Ginkgo biloba L.

QIN Chaoyi, ZHU Guoqin, WANG Jun, GAO Qi

2022, 53(02): 184-191. https://doi.org/10.16522/j.cnki.cjph.2022.02.003

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Ginkgo biloba L. is rich in shikimic acid. Modern pharmacological studies have shown that shikimic acid has antioxidant, antithrombotic, antibacterial and anti-inflammatory activities. It is the raw material for the synthesis of oseltamivir phosphate, an anti-avian influenza and anti-influenza A(H1N1) virus drug. At present, many researchers engage in expanding the sources of shikimic acid and synthesizing compounds with anticancer, antiviral and glycemic control functions, which are of great value in the field of new drug research and development. The researches on the detection and assay methods of shikimic acid in Ginkgo biloba L., the preparation, pharmacological effects and applications in the synthesis of new compounds are reviewed in this paper, which provide a reference for the further development and utilization of shikimic acid resources.

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Paper

Improved Synthetic Process of Drotaverine Hydrochloride

WANG Kai, YAN Xuran, CHEN Binghan, ZHAO Yimei

2022, 53(02): 192-195. https://doi.org/10.16522/j.cnki.cjph.2022.02.004

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Compound N-Boc-dopamine(13) prepared by protecting dopamine hydrochloride(12) with (Boc)2O was ethylated with diethyl sulfate to obtain tert-butyl (3,4-diethyloxyphenylethyl)carbamate(14), and then 14 was hydrolyzed to obtain 3,4-diethyloxyphenylethylamine(4). In addition, 1,2-diethoxybenzene(16) was obtained by ethylation of catechol(15) with diethyl sulfate. Ethyl 2-(3,4-diethoxyphenyl)-2-oxoacetate(17) was prepared by Friedel-Crafts acylation of compound 16. The key intermediate 2-(3,4-diethoxyphenyl)acetic acid(5) was obtained from compound 17 by Huangminglong reaction in the presence of KOH / hydrazine hydrate. The acyl chloride compound of 5 was condensed with compound 4 for a further cyclization reaction to obtain drotaverine hydrochloride(1) with an overall yield of 60.4％(based on 12). The synthetic route was simple, safe and easy to operate, without high temperature, high pressure and highly toxic raw materials, and it was suitable for industrial production.

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Synthesis of the Related Substances of Lorcaserin Hydrochloride

TANG Jun, HE Guangwei, ZHANG Qiang, WANG Kui, LIU Weizhong, LIU Zijin

2022, 53(02): 196-201. https://doi.org/10.16522/j.cnki.cjph.2022.02.005

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To perform the quality control of lorcaserin hydrochloride, five related substances were prepared. These substances were 8-chloro-3-(2-chloropropyl)-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(A), (R)-8-chloro- 1-methyl-3-acetyl-1,2,4,5-tetrahydro-1H-benzo[d]azepine(B), (S)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]- azepine (2S,3S)-2,3-dihydroxysuccinate(2∶1)(C), (R)-7-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride(D), (S)-7-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride(E). The related substances A, D and E have not been reported in literature. The structures of the above related substances were confirmed by 1H NMR and MS, and the substitution position of chlorine atom as well as chiral configuration of related substance D was confirmed by single crystal X-ray diffraction, which could be used as references of lorcaserin hydrochloride quality control.

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Application of HL60/NF-κB Pyrogen Reporter Gene Assay in Detection of Pyrogen in Monoclonal Antibodies

LIU Lizhen, WANG Can, WANG Mingren, CHEN Gang, SHAO Hong

2022, 53(02): 202-207. https://doi.org/10.16522/j.cnki.cjph.2022.02.006

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A new human promyelocytic leukemia(HL-60)/nuclear factor-κB(NF-κB) reporter gene pyrogen detection method was established initially, and its application in pyrogen detection in adalimumab injection, bevacizumab injection, tocilizumab injection and daratumumab injection was discussed. And the accuracy, repeatability and sensitivity of this method were validated. The lipopolysaccharide(LPS) standard solutions with different concentrations were prepared to act on the cells under the minimum dilution factor of the four monoclonal antibody injections without interference. The logarithmic value of LPS concentration was taken as the abscissa and the chemiluminescence intensity value was taken as the ordinate, and a standard curve was fitted. The results showed that the R2 values were all greater than 0.950 0. When the concentration of LPS standard was greater than 1 EU/ml, the coefficient of variation was less than 20％, and the average detection limit of this method was 0.02 EU/ml, which provided a reference for the expansion of the pyrogen detection method for biological products.

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Exploratory Research on Dermato-pharmacokinetics of Terbinafine Hydrochloride Film-forming System

BAI Jiaqian, MA Jinlong, WANG Jian, NI Rui, HUANG Lele

2022, 53(02): 208-213. https://doi.org/10.16522/j.cnki.cjph.2022.02.007

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Taking BAMA piglet as the experimental animal model, the dermato-pharmacokinetic properties of terbinafine hydrochloride film-forming system and the commercially available product(1％ terbinafine hydrochloride cutaneous solution) were preliminarily investigated by the tape stripping method. An HPLC and a LC/MS were established for determination of drug concentration in the stratum corneum peeled off from the piglet skin on days 0 - 7 and days 7 - 14 after administration, respectively. The results showed that there were no significant differences between the self-made and reference preparations in main pharmacokinetic parameters(P>0.05). The values of cmax, t1/2 and AUC0→t for the self-made and reference preparations were (14 603.95±1 461.59) and (14 542.08±1 481.07)ng/cm2, (75.84±22.35) and (68.34±3.41)h, (920 447.88±166 949.76) and (901 108.6±141 669.28)ng·cm–2·h, respectively. The values of tmax for both preparations were 3 h. The relative bioavailability of the self-made preparation was (102.15±15.13)％.

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Dissolving and Sustained-release Effect of Poloxamer 188 Complexed Poly L-Lactic Acid Electrospun Fibers on Docetaxel

WANG Yingying, DONG Xin, SUN Limin, WANG Hao, WEN Meng

2022, 53(02): 214-224. https://doi.org/10.16522/j.cnki.cjph.2022.02.008

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The release behaviors of docetaxel from a series of Poloxamer188 composite poly L-lactic acid electrospun fibers and the effect of drug incorporation amount on its release behavior were investigated. Docetaxel, poloxamer 188 and poly L-lactic acid were all dissolved in dichloromethane to form a homogeneous solution. The composite amount of poloxamer 188 and the loading amount of docetaxel were set as 220％, 240％, 260％, 280％ and 300％ of the mass of poly L-lactic acid, and 5％, 10％ and 15％ of the mass of poly L-lactic acid. Then, a series of electrospun fibers incorporated with docetaxel were prepared by electrospinning. The observation results of scanning electron microscopy revealed that all the products were micro-scale fibers with uniform diameter and without beads structure. The results of X-ray diffraction, differential thermal analysis and infrared spectroscopy showed that docetaxel was well combined within the fibers, while poloxamer 188 separated on the fiber surfaces. By measuring the release amount of docetaxel from electrospun fibers in pure water, the release curves were drawn, and the release data obtained could be fitted with the similar form of Lagergren equation. The results also showed that docetaxel was of being solubilized during the whole release process. As poloxamer 188 composite content increased, the drug release amount slightly increased. As docetaxel loading amount increased, the drug release amount decreased significantly. When composite amount of poloxamer 188 was 300％ and the loading amount of docetaxel was 5％, cumulative release of the drug at 672 h in pure water was 59.36％, and its absolute release was 7.3 μg/mg fiber.

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Formulation Optimization and in vitro Release of Diosmetin Liposomes

GUO Jiabin, XU Wenxia, LI Honglian, SUN Wenxia, REN Jing

2022, 53(02): 225-232. https://doi.org/10.16522/j.cnki.cjph.2022.02.009

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The liposomes loaded with diosmetin were prepared by thin film ultrasonic dispersion method to improve poor water-soluble of diosmetin. With encapsulation efficiency and particle size as main indicators, single factor tests were carried out to find the test ranges of formulation and process parameters, followed by further optimization with response surface methodology coupled with Box-Behnken design. The optimal formulation and process parameters were as follows: lipid-drug ratio(namely the mass ratio of soybean phospholipids to diosmetin) was 5.26, cholesterol mass was 6.31 mg, and phospholipid concentration after hydration was 1.19 mg/ml, ultrasonic treatment of the obtained hydration liquid was conducted at 360 W for 2 min. The particle size, ζ potential, encapsulation efficiency and drug loading of the final diosmetin liposomes were (146±3)nm, (–38.63±0.13)mV, (88.2±1.2)％ and 14.6％, respectively. The transmission electron microscopy analysis revealed that the liposomes were uniform in size and spherical in shape. The in vitro cumulative release at 48 h was 79.68％, and the diosmetin release behavior was conformed to the Weibull's equation(r=0.995 0).

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Preparation and in vitro Evaluation of Silybinin Nanosuspension

ZHANG Ling, CHENG Jiahui, CHANG Jinhua, LIU Xigang

2022, 53(02): 233-239. https://doi.org/10.16522/j.cnki.cjph.2022.02.010

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To improve the dissolution rate of insoluble drug silybinin, the silybinin nanosuspension(Sy-NS) was prepared by high pressure homogenization method. The formulation factors(such as the stabilizer, adding amount of drug and lyoprotectant) and process parameters were optimized with particle size and polydispersity index(PDI) as indicators. The results showed that the optimal nanosuspension was obtained by high pressure homogenization with sodium dodecyl sulfate(SDS) and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer(Soluplus) as the composite stabilizer and the mass ratio between drug, SDS and Soluplus of 60∶1∶9. The particle size and PDI of the freeze-dried product with the combination of 6％ sucrose and 1％ mannitol as lyoprotectants were 409.3 nm and 0.332. And no significant change in particle size was observed after lyophilization. The dissolution behaviors of Sy-NS, physical mixture and silybinin in aqueous solution containing 0.5％ SDS were investigated, and the calculated dissolution rate at 2 h were 61.8％, 31.9％, and 26.5％, respectively. The results of infrared spectroscopy(IR), differential scanning calorimetry(DSC) and X-ray diffraction(XRD) showed that the state of silybinin was changed during the preparation process.

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Identification of Fermented Cordyceps Powder Capsules Based on Capillary Electropherogram of the Partial Acid Degradation Products of Polysaccharides

ZHANG Jian, MA Mengnan, XIE Xiaoying, LU Kai, GUO Huaizhong

2022, 53(02): 240-245. https://doi.org/10.16522/j.cnki.cjph.2022.02.011

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A capillary zone electrophoresis(CZE) method was established to determine the partial acid degradation products of polysaccharides in fermented Cordyceps powder(FCP). Degradation products were derived using 1-phenyl-3-methyl-5-pyrazolone(PMP). The uncoated flexible fused silica capillary column was used, with 40 mmol/L sodium tetraborate buffer(pH 10.1) as the running buffer. The detection wavelength was 245 nm, the operating voltage was 17 kV, and gravity injection(10 cm×15 s) was used for measurement. And the partial acid degradation conditions of Cordyceps polysaccharides were optimized by the single factor experiment and orthogonal design. The results showed that the optimized conditions were as follows: the concentration of hydrochloric acid was 0.8 mol/L, the degradation temperature was 80 ℃, and the degradation time was 4 h. The CZE spectra of the partial acid degradation products of polysaccharides in different FCP capsules were significantly different, with strong characteristics, and accurate classification was achieved, which could be used for the quality control of FCP preparations from different sources, and also provided a reference for its structure-activity relationship research and quality analysis of other traditional Chinese medicine preparations.

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Integrity of Sealed Injection Bottle Container: Correlation and Comparative Analysis of Microbiological Challenge Test and Dye Ingress Method

WANG Ni, HUANG Sijia, WANG Jing, ZHANG Fangfang

2022, 53(02): 246-252. https://doi.org/10.16522/j.cnki.cjph.2022.02.012

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The correlation between the microbiological challenge test and dye ingress method on the sealing integrity of the neutral borosilicate glass controlled injection bottle container was investigated and compared. The microbiological challenge test included immersion of the sealed and sterilized empty packaging system in a suspension of high concentration of Pseudomonas aeruginosa, and driving a specific pressure for four hours. After taking it out, it was cultured at 33 ℃ for seven days. The dye ingress method was to immerse the sealed empty packaging system in a 10％ methylene blue aqueous solution, then put it in a vacuum chamber with the pressure of 75 kPa for 30 min. After returning to normal pressure, it was immersed in the methylene blue solution again for 30 min, then after flushing, it was inspected visually. The results showed that the positive detection rates of microbiological challenge test and dye ingress method for punched samples with 1, 3, 5, and 10 μm pore size were 0, 30％, 40％, 100％ and 0, 0, 4.5％, 15％, respectively. The sensitivities of the 10％ positive detection rate were 2.2 and 8.3 μm, respectively, which indicated that the sensitivity of the former method was slightly better than that of the latter for injection bottle packaging. It was hoped to provide a reference for method development and comparative analysis of container seal integrity.

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Main Chemical Components of Linggui Zhugan Decoction Based on UHPLC-QTOF/MSE

XU Yajing, WU Tong, ZHANG Zhiqiang, LIN Shan

2022, 53(02): 253-263. https://doi.org/10.16522/j.cnki.cjph.2022.02.013

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An UHPLC-QTOF/MSE method was established to analyze the main chemical components in Linggui Zhugan decoction in both positive and negative ion modes. Combined with the self-built databases and online databases, the chemical components in Linggui Zhugan decoction were identified by accurate relative molecular mass, fragment ion information, fragmentation law and comparison with the reference substances. In addition, the attribution of each compound was realized by using the binary comparison function of UNIFITM. As a result, a total of one hundred compounds were identified from Linggui Zhugan decoction, including six amino acids, four carbohydrates, eleven small molecular organic acids, twenty-seven flavonoids, forty saponins and twelve other components. It showed that the pharmacologically active chemical substances in Linggui Zhugan decoction and the characteristic components of each medicinal material were comprehensively reflected, which provided a data reference for the rapid identification, quality control and clinical application of the chemical substances in Linggui Zhugan decoction.

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Pharmaceutical Management & Information

Current Status and Thoughts on the Mechanism of Drug Centralized Procurement by Local Government

TANG Di, DING Jinxi, CHEN Ye

2022, 53(02): 264-271. https://doi.org/10.16522/j.cnki.cjph.2022.02.014

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Pharmaceutical Management & Information

A Brief Comment on the FDA's Regulatory Concept and Promotion Measures of Emerging Technologies

CHEN Yuan, DONG Jiangping