[Manufacturing classification system for oral solid dosage forms of traditional Chinese medicines(â ): classification of processing routes].

Oral solid dosage(OSD) occupies a key position in the market of Chinese patent medicines and new traditional Chinese medicines. Processing route is the foundation for the research and development of traditional Chinese medicine OSDs. On the basis of prescriptions and preparation methods of 1 308 traditional Chinese medicine OSDs recorded in the Chinese Pharmacopoeia, we summarized the patterns of processing routes of both modern dosage forms(tablets, granules, and capsules) and traditional dosage forms(pills and powder) and constructed a manufacturing classification system(MCS) based on the processing routes. Based on the MCS, statistical analyses were conducted respectively on medicinal materials, pharmaceutical excipients, extraction solvents in the pretreatment process, crushed medicinal materials, methods of concentration and purification, and methods of drying and granulation, aiming to uncover the process features. The results showed that each dosage form can be prepared via different routes with different processing methods of decoction pieces and raw materials for dosage preparation. The raw materials for dosage form preparation of traditional Chinese medicine OSDs included total extract, semi-extract, and total crushed powder, which accounted for different proportions. The raw materials for traditional dosage forms are mainly decoction pieces powder. Semi-extracts are the main raw materials for tablets and capsules, which account for 64.8% and 56.3%, respectively. Total extracts are the main raw materials for granules, with a proportion of 77.8%. Compared with tablets and capsules, traditional Chinese medicine granules with dissolubility requirements had a larger proportion of water extraction process, a higher proportion of refining process(34.7%), and a lower proportion of crushed medicinal mate-rials in semi-extract granules. There are four ways to add volatile oil to the modern dosage forms of traditional Chinese medicine. In addition, some new technologies and processes have been used in concentration, filtration, and granulation processes of traditional Chinese medicine OSDs, and the application of pharmaceutical excipients is diversified. The results of this study are expected to provide reference for the processing route design and upgrading of OSDs for new traditional Chinese medicines.

[Material manufacturability classification in high shear wet granulation process of Chinese medicine].

The high shear wet granulation(HSWG) process of Chinese medicine has a complicated mechanism. There are many influencing factors that contribute to this process. In order to summarize the manufacturability of different kinds of materials in HSWG, this paper constructed a material library composed of 11 materials, including 4 Chinese medicine extracts and 7 pharmaceutical excipients. Each material was described by 22 physical parameters. Several binders were employed, and their density, viscosity and surface tension were characterized. Combining empirical constraints and the principle of randomization, 21 designed experiments and 8 verification experiments were arranged. The partial least squares(PLS) algorithm was used to establish a process model in prediction of the median granule size based on properties of raw materials and binders, and process parameters. The surface tension and density of binders, as well as the maximum pore saturation were identified as key variables. In the latent variable space of the HSWG process model, all materials could be divided into three categories, namely the Chinese medicine extracts, the diluents and the disintegrants. The granulation of Chinese medicine extracts required low viscosity and low amount of binder, and the resulted granule sizes were small. The diluent powders occupied a large physical space, and could be made into granules with different granule sizes by adjusting the properties of binders. The disintegrants tended to be made into large granules under the condition of aqueous binder. The combination use of material database and multivariate modeling method is conducive to innovate the knowledge discovery of the wet granulation process of Chinese medicine, and provides a basis for the formulation and process design based on material attributes.

Integration of Metabolomics and Transcriptomicsto Comprehensively Evaluate the Metabolic Effects of Gelsemium elegans on Pigs.

Some naturalphytogenic feed additives, which contain several active compounds, have been shown to be effective alternatives to traditional antibiotics. Gelsemium elegans (G. elegans) is a whole grass in the family Loganiaceae. It is a known toxic plant widely distributed in China and has been used as a traditional Chinese herbal medicine for many years to treat neuropathic pain, rheumatoid pain, inflammation, skin ulcers, and cancer. However, G. elegans not only is nontoxic to animals such as pigs and sheep but also has an obvious growth-promoting effect. To our knowledge, the internal mechanism of the influence of G. elegans on the animal body is still unclear. The goal of this work is to evaluate the metabolic consequences of feeding piglets G. elegans for 45 days based on the combination of transcriptomics and metabolomics. According to growth measurement and evaluation, compared with piglets fed a complete diet, adding 20 g/kg G. elegans powder to the basal diet of piglets significantly reduced the feed conversion ratio. Results of the liver transcriptome suggest that glycine and cysteine-related regulatory pathways, including the MAPK signaling pathway and the mTOR signaling pathway, were extensively altered in G. elegans-induced piglets. Plasma metabolomics identified 21 and 18 differential metabolites (p < 0.05) in the plasma of piglets in the positive and negative ion modes, respectively, between G. elegans exposure and complete diet groups. The concentrations of glycine and its derivatives and N-acetylcysteine were higher in the G. elegans exposure group than in the complete diet group.This study demonstrated that G. elegans could be an alternative to antibiotics that improves the immune function of piglets, and the latent mechanism of G. elegans may be related to various signaling pathways, including the MAPK signaling pathway and the PPAR signaling pathway.

Comparative toxicokinetic profiles of multiple-components of Gelsemium elegans in pigs and rats after a single oral administration.

Gelsemium elegans Benth (G. elegans) is highly toxic to humans and rats, but has insecticides and growth promoting effects on pigs and goats. G. elegans is widely used in livestock, but its in vivo dynamics are entirely unknown. Hence, we investigated the toxicokinetic profiles of G. elegans alkaloids after a single oral dose of G. elegans to pigs (1.0 g/kg) and rats (0.1 g/kg). The results indicated that rats were more susceptible to the toxicity of G. elegans than pigs. The toxicokinetic parameters of 22 and 6 components were obtained in pigs and rats, respectively. The components included 9 and 5 gelsedine-type alkaloids in pigs and rats, respectively. The Tmax results of the 5 gelsedine-type alkaloids indicated that these alkaloids were rapidly absorbed in pigs and rats. The T1/2 values of the 5 gelsedine-type alkaloids indicated that the elimination rates of these alkaloids in pigs were slower than those in rats. In addition, the Cmax and AUC results indicated that the degrees of absorption and exposure of most alkaloids in pigs were higher than those in rats except GS-2. However, the Cmax value of GS-2 (11-methoxy-14-hydroxygelsenicine) in rats was greater than that of pigs, and the Cmax value of 14-hydroxygelsenicine in pigs was merely greater than 3 times that of rats. The present results suggested that the cause of the toxicological differences species of G. elegans might be related to the degrees of absorption and exposure of gelsedine-type alkaloids, especially for the 14-hydroxygelsenicine and GS-2 in different animals.

Pharmacokinetic Study of Multiple Components of Gelsemium elegans in Goats by Ultra-Performance Liquid Chromatography Coupled to Tandem Mass Spectrometry.

Gelsemium elegans (G. elegans) has been used in traditional Chinese medicine. This plant is highly toxic to humans, but can promote the growth of pigs and goats in the veterinary clinic. It is a very complex mixture containing tens or hundreds of different components. Therefore, multiple-component pharmacokinetic studies of G. elegans are a major challenge due to the lack of authentic standards of the components. The purpose of this study was to investigate the plasma pharmacokinetics of multiple components after a single oral dose of G. elegans in goat using a sensitive ultra-performance liquid chromatography coupled to tandem mass spectrometry method for the simultaneous semiquantification of multiple alkaloids without standards. The method was validated in terms of the specificity, LOD, LOQ, linearity, accuracy, precision and matrix effects. To validate the global pharmacokinetic characteristics, the results obtained from the semiquantitative analysis of three authentic compounds (gelsemine, koumine and humantenmine) were compared with the absolute quantification from our recently published method. The results showed that the two methods had similar analytical results, and the obtained values of Tmax, T1/2 and MRT0-t of the three alkaloids were similar between the two methods. In addition, the values of Cmax and AUC0-t of the three alkaloids after normalization were close to the real values, which indicated that this semiquantitative method could be used in the pharmacokinetic study of multiplecomponents. Then the pharmacokinetic parameters of 23 other G. elegans alkaloids in goats were obtained. The results suggested that the gelsedine-type alkaloids were the major active ingredients that predict and explain the efficacy and toxicity of G. elegans.

An analytical strategy to explore the multicomponent pharmacokinetics of herbal medicine independently of standards: Application in Gelsemium elegans extracts.

The multicomponent pharmacokinetic study of herbal medicine is a great challenge due to the low plasma concentrations, large range of concentration scales, lack of authentic standards and uncertain interactions of the components. The aim of this work was to explore the in vivo pharmacokinetics of herbal medicine independently of authentic standards using an integrated analytical strategy. First, ion pairs of multiple components were tuned and selected, and then major parameters were optimized for derivative multiple reaction monitoring (DeMRM) by LC-MS/MS, which was combined with characterization of the chemical profiles of the herbal medicine by LC-QqTOF/MS. Second, different concentrations of herbal extracts were employed instead of authentic standards to construct calibration curves for the semiquantitative determination of multiple components in plasma. Taking Gelsemium elegans as an example, in addition to the fully validated and sufficient methodological results, a total of 27 alkaloid components, major bioactive constituents of Gelsemium elegans, were simultaneously monitored in pig plasma. The concentration-time profiles and pharmacokinetic properties of these 27 components were characterized. The absolute quantification of three components was compared with the results obtained using authentic standards, and the method showed very similar analytical characteristics, such as linearity, precision, accuracy, and the values of the pharmacokinetic parameters Tmax, Vd, Cl and MRT. This analytical strategy was found to be capable of assessing herbal pharmacokinetics independently of specific authentic compounds for each component. This study was the first attempt to systematically reveal the in vivo pharmacokinetics of Gelsemium elegans. This strategy and methodology will find widespread use in the quantitative pharmacokinetic analysis of multiple components independently of standards for herbal medicine, among other applications.