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Shuo Shen, Shu-Zhi Liu, Yu-Shi Zhang, Mao-Bo Du, Ai-Hua Liang, Li-Hua Song, Zu-Guang Ye Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China Abstract: Malaria is still a serious public health problem in some parts of the world. The problems of recurrence and drug resistance are increasingly more serious. Thus, it is necessary to develop a novel antimalarial agent. The objectives of this study were to construct a novel compound antimalarial transdermal nanosystem–ethosomal cataplasm, to investigate its characteristics and efficiency, and to systematically explore the penetration-enhancing mechanisms of ethosomal cataplasm. Artesunate-loaded ethosomes and febrifugine-loaded ethosomes were prepared, and their characteristics were evaluated. Drug-loaded ethosomes were incorporated in the matrix of cataplasm to form the compound antimalarial ethosomal cataplasm. With the help of ethosomal technology, the accumulated permeation quantity of artesunate significantly increased at 8 hours after administration, which was 1.57 times as much as that of conventional cataplasm. Soon after administration, the ethosomal cataplasm could make a large quantity of antimalarial drug quickly penetrate through skin, then the remaining drug in the ethosomal cataplasm could be steadily released. These characteristics of ethosomal cataplasm are favorable for antimalarial drugs to kill Plasmodium spp. quickly and prevent the resurgence of Plasmodium spp. As expected, the ethosomal cataplasm showed good antimalarial efficiency in this experiment. The negative conversion rates were 100% and the recurrence rates were 0% at all dosages. The mechanism of penetration enhancement of the ethosomal cataplasm was systematically explored using an optics microscope, polarization microscope, and transmission electron microscopy. The microstructure, ultrastructure, and birefringent structure in skin were observed. Data obtained in this study showed that the application of ethosomal technology to antimalarial cataplasm could improve the transdermal delivery of drug, enhance the efficacy, and facilitate practical application in clinic. Keywords: ethosomes, transdermal drug-delivery systems, artesunate, febrifugine

The lipopolysaccharide(LPS)-indused RAW264.7 cells inflammation model was used as a carrier to investigated the effects of the preparation quality markers of Yulian Tang with anti-inflammatory activity in vitro. RAW264.7 cells were treated with LPS(50 ng·mL~(-1)) or/and different concentrations(low dose 0.1 μmol·L~(-1); medium dose 1 μmol·L~(-1); high dose 10 μmol·L~(-1)) of 18 chemical components in Yulian Tang for 24 h. Then the activity of RAW264.7 cell was detected using Cell Counting Kit-8(CCK-8) and the concentrations of inflammatory factors TNF-α and IL-6 in the supernatant of RAW264.7 cell were detected by ELISA assay. As the concentrations of chemical components in Yulian Tang increased, berberine, coptisine, magnoflorine, epiberberine, columbamine and costunolide had stronger inhibitory effects on TNF-α, whereas limonin, dehydroevodiamine, chlorogenic acid, neochlorogenic acid, groenlandicine, evodiamine, rutaecarpine and phellodendrine showed weakened inhibitory effects on TNF-α. The concentrations of palmatine, jatrorrhizine, dehydrocostus lactone and cryptochlorogenic acid had no significant effect on their inhibitory effect on TNF-α. Furthermore, dehydrorutaecarpine, chlorogenic acid, neochlorogenic acid, evodiamine, rutaecarpine, costunolide, phellodendrine and cryptochlorogenic acid showed stronger inhibitory effect on IL-6 as their concentrations increased; berberine, coptisine, magnoflorine, epiberberine, limonin, columbamine, groenlandicine and dehydrocostus lactone had no changes in their inhibitory effects on IL-6 as the concentrations increased. Palmatine and jatrorrhizine had the best inhibitory effect on IL-6. Combining the previous analysis of qualitative and quantitative preparation quality markers of Yulian Tang with the above result of dose-response relationship, we finally identified 15 preparation quality markers of Yulian Tang with anti-inflammatory activity, namely berberine, coptisine, palmatine, magnoflorine, epiberberine, limonin, columbamine, jatrorrhizine, neochlorogenic acid, chlorogenic acid, groenlandicine, evodiamine, rutaecarpine, dehydrocostus lactone and costunolide. In conclusion, our study provides a quick strategy for screening the qualitative preparation quality markers of Yulian Tang with anti-inflammatory activity. Moreover, it also provides an explicit route for the determination of preparation quality markers of Yulian Tang with other activities.

On the basis of the qualitative preparation quality markers of Yulian Decoction, we screened out the quantitative markers and explored a general strategy for analyzing the component migration in Chinese herbal pieces, preparations, and plasma. A method capable of simultaneously determining 28 chemical components in Yulian Decoction was established based on HPLC-MS/MS. This method was used to determine the migrated components in herbal pieces-lyophilized powder preparations-rat plasma after administration of Yulian Decoction. Liquid chromatography was performed under the following conditions: C_(18)-reversed phase chromatographic column(2.1 mm × 100 mm, 1.8 μm); acetonitrile-water(containing 0.1% formic acid) as the mobile phase for gradient elution; the flow rate of 0.2 mL·min~(-1). Electrospray ionization source was adopted for mass spectrometry detection, in which positive and negative ion modes and multiple reaction monitoring were applied. Confirmed by the methodological investigation in linear range, recovery(95.48%-103.4%), precision(RSD, 0.45%-3.8%), stability, and repeatability(RSD, 5.6%-14%), the established method was suitable for the detection and quantification of the components in Yulian Decoction. The results showed that in the lyophilized powder of Yulian Decoction, berberine was greater than 5% in mass fraction, magnoflorine, epiberberine, coptisine, palmatine, and limonin in the range of 1%-5%, and dehydroevodiamine, evodiamine, rutaecarpine, costunolide, and dehydrocostus lactone in the range of 0.002%-1%. Of the 28 components detected in pieces, 27 were found to migrate to the lyophilized powder, and 11 were detected in rat plasma. Fifteen components were preliminarily determined as quantitative preparation quality markers for Yulian Decoction, including berberine, epiberberine, coptisine, palmatine, evodiamine, rutaecarpine, limonin, costunolide, dehydrocostus lactone, magnoflorine, jatrorrhizine, columbamine, groenlandicine, chlorogenic acid, and neochlorogenic acid. In conclusion, the HPLC-MS/MS general strategy was established for analyzing the migration of multiple components in Chinese herbal pieces, preparations, and plasma, which can provide the basis for the screening of quantitative preparation quality markers and multi-index quality control of Yulian Decoction.

Objective: To observe the effect of acupoint application of gel plaster on quality of sleep and life in patients with insomnia., Methods: A total of 63 patients with insomnia were randomized into a gel plaster group (32 cases, 1 case dropped off) and a placebo plaster group (31 cases). Acupoint application of gel plaster was applied at Yintang (GV 29) and Yongquan (KI 1) in the gel plaster group, placebo plaster was applied at the same acupoints in the placebo plaster group. The treatment was given from bedtime to early moming of the next day, 5 days were as one course, with 2-day interval, totally 4 courses were required in the both groups. Pittsburgh sleep quality index (PSQI), Epworth sleepiness scale (ESS) and Flinders fatigue scale were used to evaluate the sleep quality and fatigue level of the patients in the both groups before and after treatment and at 2 weeks of follow-up. The variations of insomnia TCM syndrome score and the 36-item short-form health survey (SF-36) score before and after treatment were observed., Results: Compared before treatment, the scores of PSQI, ESS and FFS after treatment and at follow-up were decreased in the both groups ( P <0.01), and the variations of PSQI total scores and ESS scores in the gel plaster group were larger than those in the placebo plaster group ( P <0.05). Compared before treatment, the insomnia TCM syndrome scores were decreased ( P <0.01), the scores of physiological function, physiological role, general health, role emotion, mental health of SF-36 were improved after treatment in the both groups ( P <0.05), and the social function score after treatment in the gel plaster group was superior to that in the placebo plaster group ( P <0.05)., Conclusion: Acupoint application of gel plaster can effectively improve the quality of sleep and life in patients with insomnia.

This article aimed to discuss,the dosage problems in the first 100 published classic prescriptions,mainly on the dosage units involved in Treatise on Febrile Diseases. The dosage units were mainly classified into three types: weight unit,volume unit and length unit. The volume unit and length unit are basically not controversial. The weight unit is more problematic. Through textual research,measured data and the calculation by State Administration of Taxation on unearthed cultural relics,the basis for the weights and measures in the Han Dynasty was clarified,namely glutinous rice( Shu). The Zhu-Liang system was adopted for weight measurement,and the weight of glutinous rice( Shu) was used to measure the weight of others, " 1 Liang = 24 Zhu = 240 Lei = 2 400 Shu". Sheng-He system was adopted for volume measurement,and the volume of the glutinous rice( Shu) was used to measure the volume of others, " 1 Sheng = 10 He = 20 Yue = 24 000 Shu". The width of the glutinous rice( Shu) was used to measure the length, " 1 Chi = 10 Cun =100 Fen = 100 Shu". At the same time,the conversion relationship between ancient dosage units in Treatise on Febrile Diseases and modern dosage units was clarified in this paper, " 1 Jin = 250 g,1 Liang = 15. 625 g,1 Zhu = 0. 65 g", " 1 He = 20 m L,1 Sheng =200 m L", " 1 Chi = 23 cm,1 Cun = 2. 3 cm". Through research,it is found that the weight measurement in the Han Dynasty was " glutinous rice system",which was based on " glutinous rice",providing a powerful key to solve the weight disputes in the classic prescriptions. Through the combination of textual research and physical testing,disputes can be eliminated more quickly,and an " expert consensus" can be formed on the weight issues. The definite drug dosage in Treatise on Febrile Diseases can provide convenience for the clinical prescription system,and provide a dose basis for the development of the classic preparations.

Classical Representative Famous Prescription is the valuable cultural heritage of Chinese medicine. In November 2018,the State Council issued the " Intensive Implementation of the National Intellectual Property Strategy in 2018 to Accelerate the Construction of IP Strong Country",explicitly proposing to strengthen the intellectual property protection of Classical Representative Famous Prescription.How about the current situation of intellectual property protection of lassical Representative Famous Prescription in China? We selected Liuwei Dihuang Pills,Shengmai Powder and Guizhi Fuling Pills( three representative drugs on market) from Chinese Pharmacopoeia2015 Volume I issued by Chinese Pharmacopoeia Commission to analyze their patent layout,reflecting its status quo of patent protection as follows: first,in recent years,the number of related patent applications for Classical Representative Famous Prescriptions has declined,which was positively correlated with the drug registration and approval policies in recent years,but the policy dividend has not been reflected in the patent application,which may be related to the long period of pharmaceutical R&D; secondly,the patent applicant in the field of Chinese medicine is mainly based on individuals,but the applicant of Classical Representative Famous Prescription is mainly of enterprises,and in addition,the company applicants have the highest authorization rate; thirdly,the main technologies are to improve preparation method and the dosage form in the research and development of Classical Representative Famous Prescription,but these two types of authorized patents have much difficulty in further application on the market. Therefore,the innovative entities shall look for a new breakthrough in secondary development and utilization of Classical Representative Famous Prescriptions.

In this paper, classic preparations in Treatise on Febrile Diseases were systematically investigated to obtain their process parameters, and provide literature evidence and technical support for drug research and development. This paper includes the following sections: drug dose, solvents, excipients, and process parameters of classic preparations. The drug dose in Treatise on Febrile Diseases was not consistent with that in Pharmacopoeia of the People's Republic of China 2015, for example, "Yi-Liang" was about 15.625 g, and "Yi-Sheng" was about 200 mL. The solvents of classic preparations can be divided into two types: wine and water. There were eight kinds of water: water, "Dongliu water" "Ganlan water" "acid pulp" "Jinghua water" "Lao water" "Mafei Tang" "spring water". There four kinds of wines: "wine" "Bai wine" "Qing wine" "Ku wine". There were two kinds of excipients: rice and honey. Classic prescription powder had two kinds of processes: "whole prescription powder" and "Yidaoshai Hezhizhi powder". Classic prescription pills had three kinds of processes: direct whole prescription pilling, pilling after extraction, and pilling with excipients after smashing. Classic prescription decoction had six kinds of processes: "wine Tang", "Mafei Tang", "Jingmi Tang", "Mijian Tang", "water Tang" "Zhugao Tang". Drug dose, solvents, excipients, processes and other key parameters of classic preparations were systemically reviewed in this study, and the process parameters were clarified to provide literature evidence and technical support for drug development., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

In this review, the authors summarized the drugs in treatment of the age-related macular degeneration (AMD or ARMD), including the pathogenesis of the age-related macular degeneration at home and abroad, dosage forms used in the treatment, and the drugs research and development directions in the future. AMD disease is the third largest blinding diseases all over the world, with an incidence of 6.62%. The dosage form of the traditional medicine is mostly oral formulations, playing a role in body, while the newly dosage form is topical drug delivery formulation. Traditional Chinese medicine (TCM) has certain advantages in the treatment of AMD disease and the development of topical drug delivery preparations with newly preparation technologies would have a very bright prospect in the future., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

To evaluate in vitro release and transdermal behaviors of Huoxue Zhitong gel, modified Franz diffusion cell methods was applied to investigate in vitro transdermal absorption of Huoxue Zhitong gel and the content of paeonolan in receptor fluid composed of PEG400%-95% ethanol-water (l:3:6)were determined by HPLC. The results were processed and different equations were fitted. The release law were in accordance with Weibull equation and the fitting equation was In[-1/(1 - Q)] = -0.790 51nt - 1.7012 (r = 0.9809). In 8 hours, cumulative release of paeonol was 85. 18% and the release rate was 2.827 µg . cm-2 h-1. Transdermal actions were consistent with zero-level model fit and the fitting equation was Q(t) = 1.7579t + 0. 7213 (r = 0.9991). In 8 hours, cumulative transdermal rate and transmission rate of paeonol was 54. 85%, 1. 820 µg . cm-2 h-1. So the Huoxue Zhitong gel had a good release and transdermal properties.

Objective: To study the transdermal behavior of Xiaozheng Zhitong cataplasm in rats., Method: With tetrahydropalmatine as the index, the Franz diffusion cell method was adopted for the experiment. Sample content was determined with HPLC., Result: The transdermal permeability and the transmission rate of tetrahydropalmatine accumulated for 24 h were 20.20% and 0.744 1 microg x cm(-2) x h(-1), respectively., Conclusion: The transdermal behaviors of Xiaozheng Zhitong cataplasm were ideal in conformity with the zero order kinetic model.

To evaluate in vitro release and transdermal behaviors of Zhitong cataplasm, modified Franz diffusion cell method was applied to investigate in vitro transdermal absorption of Zhitong cataplasm and the content of tetrahydropalmatine was determined by HPLC. In 24 hours, accumulative release rate of tetrahydropalmatine was 81. 9%, transmission rate was 2.26 microg x cm(-2) x h(-1). In 48 hours, accumulative transdermal rate and transmission rate of tetrahydropalmatine were 20.31%, 0.22 pg x cm(-2) x h(-1). So Zhitong cataplasm had a good release and transdermal properties and transdermal actions were consistent with zero-order kinetics process.

Objective: To establish a LC-MS/MS method for determining the concentration of tanshinone IIA, salvianolic acid B and paeoniflorin of refined coronary cataplasm in rabbit plasma, in order to determine the concentration of the three main ingredients in blood after transdermal administration and calculate their pharmacokinetic parameters., Method: Rabbits were given refined coronary cataplasm on the basis of 15 g x kg(-1) by transdermal administration to detect the plasma concentration of the three main ingredients using LC-MS/MS. Winnonlin software was used to calculate their major pharmacokinetic parameters., Result: Tanshinone IIA, salvianolic acid B and paeoniflorin showed good linearity (r>0.999) at 1-100, 50-1 000, 10-1 000 microg x L(-1) respectively in plasma, with average recovery rate of 96.57%, 91.90%, 95.93%, respectively. The RSD within day were less than 15%. After transdermal administration of refined coronary cataplasm in rabbits, the main pharmacokinetic parameters of tanshinone IIA, salvianolic acid B or paeoniflorin were as follows: Cmax (20.85 +/- 12.68), (636.25 +/- 386.91), (787.80 +/- 395.64) microg x L(-1); Tmax (0.49 +/- 0.28), (0.44 +/- 0.27), (0.46 +/- 0.30) h., Conclusion: The LC-MS/MS method is highly selective and sensitive to determine the concentration of samples in rabbit plasma. The pharmacokinetic characteristics of tanshinone IIA, salvianolic acid B and paeoniflorin are suitable to assess the percutaneous absorption of refined coronary cataplasm.