Diterpene synthases from plants are key enzymes in diterpene biosynthesis, which catalyzed the initial cyclization cascade of (E, E, E,)-geranylgeranyl pyrophosphate, and generated diverse carbon skeletons. Recent research show that the structural and stereo chemical differences lead to diverse natural diterpene compounds of plants. The structures of diterpene synthases play a crucial role in cyclization function. This article mainly reviews the mechanisms, functional characteristics, and structural information of diterpene synthases according to the crystal structures and functions.

Plant flowering regulation is an important mechanism to response to environmental stress. Heat shock protein 70 family is one of the main molecular chaperones to resist stress; miRNA can be used as a negative regulator to participate in post-transcriptional gene in flowering network. In this paper, we obtained an Hsp70 gene from Lonicera japonica transcriptome and combined with Lonicera japonica miRNA library to obtain a novel miRNA that may target Hsp70 gene through bioinformatics method. Bioinformatics and expression during different flowering stages of the obtained Hsp70 gene and miRNA were analyzed. Phylogenetic tree showed that the obtained Hsp70 gene was clustered with Hsp110 subfamily in Oryza sativa and Arabidopis thaliana. The prediction of miRNA secondary structure showed its stable structure and high reliability. The binding site map showed that there were two base mismatches between sequences of miRNA and Hsp70 gene. The expression analysis showed that the expression of Hsp70 and miRNA in different flowering stages had opposite trends, indicating that miRNA might regulate Hsp70 to participate in the flowering stages of Lonicera japonica. This study provided new ideas for Lonicera japonica flowering regulation and response to environmental stress mechanisms.

MCT is an important key enzyme in the terpenoid biosynthesis in MEP pathway. In this study, Gateway technology was used to construct RNAi vector of TwMCT, and a vector fragment with a size of 484 bp was obtained. The TwMCT RNAi vector was transferred into the suspension cells of Tripterygium wilfordii by gene gun. Accumulation of terpenoids was assayed by UPLC, and the result showed that the content of triptolide and celastrol in cells decreased by 23.4% and 42.8%, respectively, compared with the control group pK7GWIWG2D. Moreover, the gene expression of TwMCT and major genes in terpenoid biosynthesis pathway was detected by qRT-PCR, which demonstrated that the expression of TwMCT reduced by 29.2% relative to that of the control group pK7GWIWG2D, and the relative expression of TwDXR, TwGGPS, TwHMGR and TwHMGS diminished by 36.3%, 31.3%, 62.2%, and 29.1%, respectively, but the expression of TwDXS was up-regulated by 114.2%, and there was no significant change in TwFPS. Thus, it was verified in vivo that interference with TwMCT expression significantly inhibited the accumulation of triptolide and celastrol in Tripterygium wilfordii, laying a foundation for further exploring the regulation mechanism of MCT gene on the terpenoid biosynthesis in Tripterygium wilfordii.

The commonly used traditional Chinese medicines Curcumae Rhizome (Ezhu) and Curcumae Radix (Yujin), are representatives of multi-plant sources. The relationship among the original source plant species is intricate. In this study, by using multivariate data analysis, volatile metabolites in rhizomes and radixes of source plants of Curcumae Longae rhizome (Jianghuang), Yujin and Ezhu in traditional Chinese medicine were compared and analyzed. The source plants included Curcuma longa, Curcuma kwangsuensis, Curcuma wenyujing and Curcuma phaeocaulis. The results indicated that:① volatile metabolites were similar in quality but variation in quantity for rhizomes and radixes origin from the same plant species; ② volatile metabolites of C. longa rhizomes showed bigger difference compared with others; ③ although common volatile metabolites were observed in rhizome of C. kwangsuensis, C. wenyujing and C. phaeocaulis, the difference among them were significant; and ④ significant differences were observed for the four kinds of radixes. Results in this study revealed the differences of the four source plants species, and similar metabolites in source plants of Curcumae Rhizome (Ezhu) and Curcumae Radix (Yujin) from the level of volatile metabolites. These results provided a reference for the clinical use of the three kinds of traditional Chinese medicine.

Tripterygium wilfordii 3-hydroxy-3-methylglutaryl coenzyme-A reductase (TwHMGR) is an important regulation site in terpenoids metabolic pathway in cytoplasm which is the first speed limit enzyme of MVA pathway. In order to investigate the effects of TwHMGR on the biosynthesis of triptolide and celastrol in Tripterygium wilfordii, the overexpression of TwHMGR (OE-HMGR) was studied in this paper. We cloned the full-length of TwHMGR to construct overexpression vector by Gateway technology then delivered the expression vector into Tripterygium wilfordii suspension cells by gene gun. qRT-PCR was used to detect the expression of TwHMGR:the expression of TwHMGR was increased to 1.75 folds over the control group (empty vector:pH7WG2D) in the overexpression group. The accumulation of triptolide and celastrol in the suspension cells of Tripterygium wilfordii was detected by UPLC, revealing that:the contents of triptolide and celastrol were increased to 163.93% and 190.04% of over the control group in the overexpression group. Based on these findings, the positive effect on the accumulation of active terpenoids, triptolide and celastrol in Tripterygium wilfordii was found and the results laid a foundation of the synthetic biology research on important active terpenoids in Tripterygium wilfordii.

Dammarenediol-Ⅱ is an important precursor in the biosynthesis pathway of ginsenosides which are the main active components of Panax quinquefolius and Panax ginseng. For constructing a dammarenediol- Ⅱ-producing cell factory, the triterpenoid precursors of yeast are improved significantly by the modular pathway engineering strategy on the basis of an MVA optimized strain. The strain overexpressing Salvia miltiorrhiza SmFPS and Arabidopsis thaliana AtSQS2 could yield 67.4 mg·g^-1 squalene, accounting for about 6.74% of cell dry weight. In our further work, an Arabidopsis thaliana 2, 3-oxidosqualene synthase AtSQE2 was found to be able to increase the downstream lanosterol yield by 22-fold, reaching 47.9 mg·g^-1. Then, regulating dammarenediol-Ⅱ synthase gene expression, using anti-sense RNA technology for regulation of ERG7 in the ergosterol pathway, and optimizing fermentation process were successively performed. Finally, the synthesis flux of triterpenes was increased to 10 g·L^-1 for the first time, and we constructed an efficient cell factory that can produce 15 g·L^-1 dammarenediol-Ⅱ, which lays a solid foundation of industrial synthesis of dammarane-type ginsenosides.

Selectivity of drug action is a determinant for wide therapeutic window and less adverse response. From the viewpoint of molecular structure the conception and strategy of drug design are mainly embodied in raising selectivity. For the target-based drug discovery it is crucial to precisely obliterate detrimental targets in dimension of time and space, so as to efficaciously translate the in vitro active compounds into in vivo therapeutic medicines. To realize this translation drug molecules must be accurately transported to and destroy the harmful targets. To this end, chemical structures of drugs must be manipulated in multiple dimensions. This article attempts to concisely describe several kinds of bifunctional molecules for raising selectivity from the standpoint of medicinal chemistry. The bifunctionality of antibody-drug conjugates (ADCs) involves in the guidance and carrier of the antibody to guide ADC and reach to target cells, and simultaneously injury quality of the toxin moiety of ADC interacts with and destroys targets. Based upon target 3D structures design of irreversible inhibitors consist in connecting an appropriate electrophilic moiety to a well-defined ligand to endow the molecule with an additional ability to covalently bond to a specific amino acid residue. Hydrophobic tag (HyT), proteosis-targeting chimera (PROTAC), and degradation tag (dTAG) are new developed technologies, which are structurally characterized by bifunctionality, and mechanistically these compounds are capable of recruiting protein of interest (POI), inducing protein-protein interaction (PPI), and cleaving POI. In spite of large molecular size and the bottleneck of pharmacokinetic and physicochemical properties these technologies still have broad development prospect owing to high selectivity and wide adaptations.

Voltage-dependent anion channels (VDACs), which are located at the mitochondrial outer membrane, playing an important role in the regulation of mitochondrial energy metabolism and mitochondria- mediated apoptotic events, are considered as potential targets for tumor therapy. Studies have indicated that neurodegenerative diseases such as Alzheimer's disease (AD) generally lead to mitochondrial dysfunction. During this process, VDAC1, changing in expression, interacting with disease-related molecules, was involved in the occurrence and development of diseases. This review summarizes the characteristics and physiological functions of VDAC1, common important structural units and its role in apoptosis. The focus is on the research progress of VDAC1 in AD, as well as the effects in learning and memory related functions by modulating VDAC1 expression or function.

As a post-translational modification, protein acetylation plays an important role in the regulation of apoptosis, mitochondriopoiesis, lipid metabolism and cellular stress response. The imbalance of acetylation and deacetylation has been blamed for the tumorigenesis and malignant progression, which is gradually considered as a promising therapeutic target. Mammalian sirtuins, a NAD⁺ dependent class Ⅲ HDACs, are closely related to the development of aging, tumor, diabetes, obesity and neurodegenerative diseases. To provide a theoretical basis for the development of new anti-tumor drugs and the treatment of malignant tumors, this paper is prepared to focus on the irreplaceable role of sirtuins in tumor evolution:maintaining genomic stability, regulating energy metabolism, and facilitating tumor cells stemness. The modulator and pathways of sirtuins family and the research progress of agonists and inhibitors are also reviewed. The functions of SIRT2 in resistance, proliferation and metastasis have been highlighted.

IDO1 (indoleamine 2, 3-dioxygenase 1) is one of the most significant checkpoint in tumor immunology. Numerous studies indicates that IDO1 is abnormally expressed in breast cancer, colorectal cancer, liver cancer and other tumor tissues, participating in tumor immune escape through multiple pathways. This review is prepared to elucidate the biological function of IDO1, highlight its pivotal role in tumor evasion, and summarize IDO1 inhibitors in the clinical trials.

Phage display technology utilizes filamentous phage display proteins and polypeptides to extract a desired polypeptide or protein from a large number of variants. The antibody fragments screened and obtained by phage display library technology play an important role in disease diagnosis and treatment. This article briefly introduces the principles of phage display technology, summarizes the development of monoclonal antibodies, the development of antigenic microbial vaccines, and the application of peptide drugs. This review highlights the importance of phage display technology in the diagnosis and treatment of various human diseases such as cancer and autoimmune diseases etc.

Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disorder including mainly ulcerative colitis (UC) and Crohn's disease (CD). In China, IBD has become a common disease of the digestive system with an dramatic increase in incidence in recent years. The pathogenesis of IBD is not yet clear, and no drugs can completely cure IBD. Compared with monoclonal antibody drugs, small molecule drugs have the advantages of low cost, easy development as oral agents, and absence of immunogenicity. This review summarizes the recent research and development of small molecule immunosuppressants for IBD.

Three-dimensional (3D) printing technology is a rapid prototyping technology for designing 3D models with special shape and complex internal structure via computer-aided/controlled drawing and preparing. This technology displays the characteristics of flexible processing, rapid shaping, low operating cost and high reliability. 3D printing technology may provide new strategies and approaches for the generation of a variety of new drug delivery systems, which makes its application in pharmaceutics attractive. This review briefly introduces the process and feature of 3D printing technology in preparation field and mainly introduces the research progress in the design and engineering of related preparations in the aspects of rate-controlled drug release, time-controlled drug release and targeted drug release. The prospects and challenges of 3D printing technology in the formulation engineering are analyzed.

Supersaturated drug delivery systems (SDDS) are defined as systems that are able to generate and maintain a sustained drug supersaturation in the gastrointestinal tract, facilitating the oral absorption of drugs with poor water solubility. Supersaturated drug solution is generated from a higher energy form of the drug or rapid dissolution through various formulation options. However, supersaturated solution is a thermodynamically unstable system that can easily lead to drug precipitation, missing the aim of improving the absorption. Therefore, maintenance of the supersaturated state is essential for the development of SDDS. Polymer-based SDDS take polymers as the precipitation inhibitor, which can effectively prevent the precipitation of drugs, generating an excellent effect on maintenance of the stability of supersaturated solution. However, different polymers have distinct anti-precipitation ability, and the mechanisms of such activity supported by the polymer remain unrevealed. In this review, we summarize the research advances in the absorption-enhancing mechanisms and in vitro evaluations of polymers-based SDDS. This review provides a reference for the design of rational SDDS.

Oxcarbazepine (OXC) is a common antiepileptic drugs. In this study, one hundred and eighty four epilepsy patients with 196 observations of oxcarbazepine's active metabolite, 10, 11-dihydro-10-monohydroxy carbazepine (MHD) were collected prospectively from routine clinical monitoring. Nonlinear mixed effect modeling was employed to develop a population pharmacokinetic model of oxcarbazepine in Chinese patients with epilepsy to investigate the impact of gender, age, weight, co-medications and genetic polymorphisms of UGT2B7 c.802T > C, ABCC2 c.1249G > A, ABCC 23972C > T on pharmacokinetic characteristics of OXC. The population estimate of apparent clearance (CL/F) and apparent volume of distribution (V/F) was 1.84 L·h⁻¹ and 275 L, respectively. Gender and UGT2B7 c.802T > C affected the clearance rate of MHD significantly. The established model was:CL/F=1.84×0.848^UGT2B7×1.17^GENDER. Where the genotype of UGT2B7 c.802T > C was CC, UGT2B7=0, otherwise UGT2B7=1. When the patient was male, GENDER=1, otherwise GENDER=0. The final model was evaluated by normalized predictive distribution error (NPDE) and bootstrap method. The model was stable and reliable, which offers a powerful approach for rational use of OXC in epilepsy patients.

In this study, the effects of honokiol (HN) treatment for 24 h on lipid synthesis was examined in HepG2 cells. The parameters include intracellular lipid droplet and the expression of SREBP-1c and PNPLA3, glucose uptake, and oxidative stress including the expression of CYP2E1 and CYP4A in normal, TO901317 (TO)- and oleic acid (OA)-treated HepG2 cells. The lipid droplets were detected by oil red O staining. The glucose uptake was measured by fluorescence spectrophotometry using[2-(N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl) amino)-2-deoxyglucose, 2-NBDG] as probe. The expression levels of target genes were detected by quantitative PCR and Western blot. The results showed that:① TO (5 μmol·L^-1) and OA (0.5 mmol·L^-1) treatment increased the levels of intracellular lipid accumulation and the mRNA and protein expression of SREBP-1c and PNPLA3. After HN (10, 20, 40 μmol·L^-1) treatment for 24 h, the lipid accumulation and the expression of SREBP-1c and PNPLA3 were all decreased in the tested cells. ② OA treatment significantly suppressed glucose uptake, while HN treatment dose-dependently increased the glucose uptake in OA-treated cells. ③ Compared with control group, CYP2E1 protein level significantly decreased in the three tested cells, and CYP4A protein level significantly decreased only in OA-treated cells following HN treatment. The above results suggest that HN may attenuate lipid accumulation by suppressing the expression of SREBP-1c and PNPLA3, and reduce lipid peroxidation and insulin resistance by down-regulation of the protein levels of CYP2E1 and CYP4A in HepG2 cells with steatosis.

Present study was designed to investigate the effects and underlying antioxidant mechanism of klotho overexpression through an intracerebroventricular injection of a lentiviral vector that encoded murine klotho (LV-KL) on cerebral ischemia injury. Four weeks after the injection of lentivirus into the lateral ventricle of C57Balc/6J mice, a mouse model of global cerebral ischemia-reperfusion was established by bilateral common carotid artery occlusion (2VO). Klotho overexpression significantly improved neurobehavioral deficits and increased the number of survival neurons in the hippocampal CA1 and caudate putamen subregions. The overexpression also decreased malondialdehyde (MDA) content in brain, while mitochondrial manganese- superoxide dismutase (Mn-SOD) and catalase (CAT) expression in brain were increased. Moreover, klotho overexpression decreased Akt and forkhead box class O1 phosphorylation. These findings suggest that klotho may compensate for its aging-related decline to provide a promising therapeutic approach for the acute ischemic stroke during aging.

This study was aimed to investigate the effects of six Schisandra lignans of Wuzhi tablet (WZ, a preparation of ethanol extract of Schisandra sphenanthera) on the pharmacokinetic process of digoxin (DG, a classical P-gp substrate) after intravenous and oral administration in rats. The effect of Schisandra lignans on the transportion of DG in Caco-2 cells was further elucidated. Our data showed that the plasma concentrations of DG were increased to different extent following co-administration of schisandrin A, schisandrin B, schisandrol B and schisantherin A, respectively. Schisandrol B showed the most potent effect among the six lignans. However, schisandrin C and schisandrol A showed little effect on pharmacokinetic of DG. Schisandrol B led to 99.0% (P < 0.05) and 109.2% (P < 0.05) increase in the AUC after orally or intravenously administered of DG, suggesting that co-administration of schisandrol B induced a more potent effect on increasing hepatic bioavailability of DG than that of intestinal. Furthermore, in vitro transport experiment showed that schisandrin A, schisandrin B, schisandrol B and schisantherin A inhibited P-gp-mediated efflux of DG, suggested that these lignans inhibited the P-gp-mediated efflux of DG. In conclusion, the exposure of DG in rats was increased when co-administered with Schisandra lignans, and schisandrol B showed the strongest effect. The dramatic increase in oral bioavailability of digoxin in the presence of schisandrol B may be due to the inhibition of hepatic/renal P-gp activity.

Flavonol glycoside is in clinical trials for treatment of hyperlipidemia. An accurate and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous determination of flavonol glycoside (M0), aglycone (M1) and glucuronide conjugate (M2) in rat plasma. d₆-Flavonol glycoside was used as internal standard (IS). After extraction from the plasma by protein precipitation, the analytes and internal standard were separated on a XDB C₁₈ column (50 mm×4.6 mm, 1.8 μm) using a gradient elution procedure. The mobile phase consisted of methanol and water (0.2% formic acid) at a flow rate of 0.6 mL·min^-1. The total run time was 4.5 min. Positive electrospray ionization was performed using multiple reaction monitoring (MRM) with transitions of m/z 461.3 → m/z 299.1 for M0, m/z 299.1 → m/z 283.1 for M1, m/z 475.0 → m/z 299.1 for M2, and m/z 467.3 → m/z 305.1 for d₆-flavonol glycoside. The method was validated and successfully applied to the pharmacokinetics study of flavonol glycoside in SD rats which were given flavonol glycoside (30 mg·kg^-1) by gavage. The C_max of M0 is (341 ±106) ng·mL^-1 and AUC_0-t is (1 960 ±725) h·ng·mL^-1, while the C_max of M2 is (1 720 ±843) ng·mL^-1and AUC_0-t is (8 510 ±2 920) h·ng·mL^-1. The results suggest that flavonol glycoside existed mainly in the form of M0 and M2 in rats. After flavonol glycoside being hydrolyzed by the intestinal flora, it was absorbed in the form of aglycone and further metabolized to M2 after the first-pass effect. In this paper, the main metabolites of flavonol glycoside in rat plasma were determined for the first time, which provided a basis for the design of clinical pharmacokinetic experiment.

The study was aimed to identify the related substances of vortioxetine hydrobromide by hyphenated techniques. The separation of the six related substances was performed on a Phenomenex Luna Phenyl- Hexyl column (150 mm×4.6 mm, 3 μm) by linear gradient elution of acetonitrile and ammonium formate solution. Electrospray and atmospheric pressure chemical ionization were interfaced respectively with high resolution Q-TOF/MS for the determination of the accurate mass and elemental composition of the parent ions of the related substances, and triple quadrupole tandem mass was employed for the product mass spectra determination. The structures of the related substances were identified through elucidation of the fragment ions. Vortioxetine hydrobromide and its related substances were adequately separated under the established HPLC conditions. Six major related substances were detected and identified for the first time. The data provides a reference for optimization of the synthetic process and quality assurance of vortioxetine hydrobromide.

The study was designed to establish an LC-MS/MS method for the simultaneous determination of scutellarin and its major metabolite isoscutellarin in rat tissues and plasma, and to investigate the effect of different route of administration on the tissue distribution of scutellarin and its metabolite in rats. Rats were treated both intravenously and intragastrically with 20 and 80 mg·kg^-1 scutellarin, respectively. Blood and tissues were collected at predetermined intervals. The concentrations of scutellarin and isoscutellarin were determined by a validated LC-MS/MS method. The method was linear in concentration ranges of 10.0/5.00 - 5 000/2 500 ng·mL^-1 for scutellarin/isoscutellarin in the rat plasma and 30.0/15.0 - 10 000/5 000 ng·g^-1 in tissues with acceptable accuracy and precision. Data obtained after an intravenous administration of scutellarin to rats showed that the drug was distributed predominantly into the small intestine, bladder and kidney. The exposures of the metabolite isoscutellarin in plasma and tissue were both less than 5%of the parent drug. After an intragastric administration, stomach wall and small intestine were the preferred sites for scutellarin disposition, followed by bladder, adrenal gland and lung at concentrations significantly higher than its plasma concentration. The plasma exposure of isoscutellarin was higher than that of the parent drug, but its tissue exposure was significantly lower than that of scutellarin. The method established in this study was successfully applied to characterization of the tissue profiles of scutellarin and its metabolite in rats. The route of administration has a marked impact on the disposition of scutellarin and its metabolite in rats. Ratios of the tissue to plasma concentrations after intragastric administration were obviously higher than those after intravenous administration. Scutellarin could pass the blood-brain barrier in a marked extent, but isoscutellarin was not detected in the rat brain, which may be attributed to the fact that scutellarin is a higher-affinity substrate for OATP than isoscutellarin.

As an important drug carrier, liposome has the advantages of high biocompatibility and low immunogenicity. It has been widely used in the field of drug delivery, especially the targeted treatment of tumors. However, traditional liposomes are composed of flowing dynamic phospholipid membranes, which are easy to fuse together, resulting in aggregation and drug leakage. In addition, the lower degree of polyethylene glycol (PEG) modification also limits the targeted delivery performance of the vector in vivo. In view of the problems, a nanoparticle-targeted drug delivery system combining the inorganic carrier calcium phosphate with liposomes was designed, namely lipid calcium phosphate (LCP). Using doxorubicin (DOX) as a model drug, doxorubicin-loaded lipid calcium phosphate nanoparticles (DOX/LCP) were prepared by reverse microemulsion method, and the preparation conditions were investigated. The structure and morphology of calcium phosphate cores were observed by infrared spectroscopy, EDS spectroscopy, and transmission electron microscopy. The particle size, encapsulation efficiency, drug loading, stability and release behavior in vitro of DOX/LCP were investigated. Confocal microscopy and flow cytometry were used to qualitatively and quantitatively evaluate the uptake of DOX in drug-resistant tumor cell line MCF-7/DOX by LCP, respectively, and the thiazolium MTT colorimetric method was used to examine its cytotoxicity. LCP exhibited a typical core-shell structure with good size uniformity and dispersibility. The particle size was in (48.6 ±3.9) nm, the potential was in (-12.1 ±1.2) mV, and the encapsulation efficiency was above 80%. Moreover, it has a good stability in simulated plasma. In vitro release of LCP had a significant pH dependence. When the pH of the environment was 7.4, the cumulative release within 24 hours was less than 20%; as the pH of the release medium decreases, the release rate of DOX/LCP was accelerated gradually. Accumulated release over 24 hours exceeded 90% in the pH 4.5 medium. LCP significantly promoted the uptake and accumulation of DOX by drug-resistant cells, and the inhibition rate of drug-resistant tumors was significantly increased in vitro. The half maximal inhibitory concentrations (IC₅₀) of LCP/DOX and free DOX were 4.6 and 11.8 μg·mL^-1, respectively, and there was a significant difference between the two groups (P < 0.05). In summary, the LCP prepared in this study had a small particle size, high encapsulation efficiency and good stability. It had environmental responsiveness and potential inhibition of tumor drug resistance, which suggests a potential in the clinical application.

Microneedles is an efficient, safe and novel transdermal drug delivery technology that has attracted much attention in recent decades. Microneedles could break through the skin's stratum corneum barrier and have an especially significant effect on the transdermal delivery of water-soluble small molecules and biological macromolecules. In this paper, a rapid onset local anesthetic preparation of lidocaine hydrochloride was prepared based on dissolving microneedles, and related quality evaluations were carried out. The key quality indicators of prepared lidocaine hydrochloride dissolving microneedles such as drug loading amount, appearance morphology, mechanical properties, skin penetration performance, in vitro dissolution performance and local anesthetic efficacy were investigated with HPLC, SEM, texture analyzer, organic staining, histological section, in vitro dissolution test and pharmacodynamics experiments respectively. The drug loading of the dissolving microneedles array reached 68.19 ±1.55 mg, and the needle tip contained 3.57 ±0.21 mg. The microneedles has good needle shape and sufficient mechanical strength to penetrate into the skin, which is a prerequisite for the successful administration of the preparation. The in vitro dissolution time was 28.28 ±1.12 s. When applied to guinea pig back acupuncture model which was modified by guinea pig intradermal papules model, although the efficacy maintenance time was shorter than that of compound lidocaine cream, dissolving microneedles can be activated within 1 min, which was much faster than compound lidocaine cream. It is possible to increase the duration of drug efficacy by increasing the density of microneedles and preparing microneedles for sustained and controlled release in future studies. Lidocaine hydrochloride dissolving microneedles and its evaluation methods for local anesthesia were established systematically here for the first time. The rapid effect of anesthesia with lidocaine hydrochloride dissolving microneedles on the skin was worthy of further investigation.

The rheological properties of six compound gels that consists of kappa carrageenan (KC) and another excipient such as konjac gum were explored through comparison of their viscosity measured by the rotation method. The gel fluid type was dependent on the rheological curve fitted by the power-law equation. The effect of concentration on the viscosity of different compound gels was investigated by establishing the linear equation between their viscosity and concentration, the slope of which was used to determine the relation between viscosity and concentration of different compound gels. The viscous flow activation energy (E_η) was calculated by the Arrhenius equation, which was able to investigate the effect of temperature on their viscosity. The interaction between monomer and compound gels was also studied by measuring their viscosity. The results showed that six compound gels were pseudoplastic fluid. Among all compound gels, the KC-xanthan gum (KC-XG) solution exhibited the most obvious shear thinning, the strongest pseudoplasticity, while the smallest E_η, resulting in the best thermal stability of viscosity. Furthermore, the concentration of KC-sodium hyaluronate (KC-HA-Na) solution affected its viscosity significantly. The viscosity of six compound gels was greater than the summation of the two kinds of monomer gels, which suggests that there is a synergistic-viscosity interaction between KC and another excipient.