[Improving comprehensive retention rate of peppermint oil in freeze-dried preparation based on cyclodextrin inclusion technology].

The freeze-drying technique, characterized by low-temperature processing, is especially suitable for sensitive volatile oils with thermal instability. However, there are few studies focusing on the retention of volatile oils in the processing of freeze-dried preparations. This study evaluated the effects of different addition methods(adsorption, emulsification, solid dispersion, and inclusion) on the retention rate of the main components in peppermint oil, aiming to explore the application feasibility of freeze-dried preparations of volatile oils. Firstly, the addition method was determined based on the retention rates of menthol in four freeze-dried preparations. Secondly, an orthogonal test was designed to optimize the preparation process based on the characteristics of the preferred addition method. The results showed that the most suitable preparation form of peppermint oil was inclusion with beta-cyclodextrin(ß-CD), and the retention rate of menthol in freeze-drying was 86.36%. According to the two-step preparation process of inclusion and freeze-drying, we introduced the product of inclusion rate and retention rate, i.e., comprehensive retention rate, to determine the optimum processing parameters. The results showed that ß-CD/oil ratio of 7∶1, inclusion temperature of 40 ℃, and inclusion time of 2 h were the optimum processing parameters. The product prepared with these parameter had the comprehensive retention rate of 68.41%, retention rate of 92.53%, and inclusion rate of 73.93%. The inclusion compound was white powder with significantly increased solubility. The pre-paration process based on cyclodextrin inclusion in this study is stable and reliable and provides a new idea for ensuring the efficacy and stability of volatile components in freeze-dried preparations.

[Standardization system of industry decoction pieces based on whole process quality control concept].

Traditional Chinese medicine (TCM) decoction pieces refer to prescription drugs that can be used in clinical or preparation production after processing medicinal herbs. TCM decoction pieces industries are inherited from the culture of TCM and are important because of their independent intellectual property rights. The Chinese Pharmacopoeia (Ch. P) 2010 edition stipulated that "All drugs taken are decoction pieces", which raised the drug status to statutory law for the first time and clearly specified that TCM decoction pieces should be applied to TCM prescription deployment and production of proprietary Chinese medicines. It also pointed out that "The specifications of the decoction pieces used in the preparation should comply with the requirements of the actual process of the corresponding formulation type". For a long time, both the processing methods and the specification grades of the clinically used pieces of Chinese medicine were based on the inheritance and supported by the classical theory and method system centered on TCM processing. However, the theoretical research and specification standards of the decoction pieces used in the production of proprietary Chinese medicines based on modern industry are scarce, and this has led to a series of problems related to the industry, making the processing of decoction pieces becoming a limiting factor in the promotion of the Chinese medicine industry. Aiming at the existing problems of the TCM decoction pieces industry, this article was guided by the standardization system of TCM based on the concept of whole-process quality control, combined with the reference to the Japanese Kampo medicine industry's feeding mode and the reflection on the combination of traditional Chinese medicine processing and modern industry, as well as the study of the core law of the whole-process of TCM production, etc. Industrial decoction pieces and the idea of building a standardized system of TCM industry decoction pieces based on the whole-process quality control were discussed in this paper, which can provide insights for exploring the effective fusion between TCM processing theory and classic heritage and modern manufacturing and can provide the basis for the establishment of a standardized system for industrial decoction pieces based on whole-process quality control of TCM. It can also offer reference for the development of the advantages of geo-authentic crude drug and the establishment of high spots of industry decoction pieces.

[Standardization of preparation of rice fried Codonopsis Radix based on correlation analysis of functional component and shape index].

The quality standard of Chinese herbal medicine is the key in quality control, and the establishment of rice processing technology standard of rice fried Codonopsis Radix has important significance for the overall quality control. In this study, the color brightness (L*), red-green chromaticity coordinate (a*), yellow-blue chromaticity coordinate (b*) and total color value（E*ab）were determined by colorimeter and used as the shape indexes. Ethanol extractives, polysaccharide, lobetyolin and 5-hydroxymethyl furfural contents were determined by using high performance liquid chromatography (HPLC) and ultraviolet (UV), and used as chemical indexes in the analysis by normalization distance method. The two index methods were adopted to optimize the processing technology of rice fried Codonopsis Radix by taking processing temperature, processing time, rice types and rice dosage as factors. The correlation analysis between the two index methods was carried out by SAS 9.40 and JMP 11 software. The results showed that all the four factors had significant differences, and the best processing technology was as follows: polished round-grained rice as raw material, processing temperature at 140 °C, processing time of 10min, and the ratio of Codonopsis pilosula and rice is 100:30. Chemical indexes showed significant positive correlations with shape indexes, providing basis for the quality evaluation of rice fried Codonopsis Radix in processing.

[Discussion on research thinking of traditional Chinese medicine standardization system based on whole process quality control].

The concept of "Quality by design" indicates that good design for the whole life cycle of pharmaceutical production enables the drug to meet the expected quality requirements. Aiming at the existing problems of the traditional Chinese medicine (TCM) industry, the TCM standardization system was put forward in this paper from the national strategic level, under the guidance by the idea of quality control in international manufacturing industry and with considerations of TCM industry's own characteristics and development status. The connotation of this strategy was to establish five interrelated systems: multi-indicators system based on tri-indicators system, quality standard and specification system of TCM herbal materials and decoction pieces, quality traceability system, data monitoring system based on whole-process quality control, and whole-process quality management system of TCM, and achieve the whole process systematic and scientific study in TCM industry through "top-level design-implement in steps-system integration" workflow. This article analyzed the correlation between the quality standards of all links, established standard operating procedures of each link and whole process, and constructed a high standard overall quality management system for TCM industry chains, in order to provide a demonstration for the establishment of TCM whole-process quality control system and provide systematic reference and basis for standardization strategy in TCM industry.

[Development of whole process quality control and management system of traditional Chinese medicine decoction pieces based on traditional Chinese medicine quality tree].

The whole process quality control and management of traditional Chinese medicine (TCM) decoction pieces is a system engineering, involving the base environment, seeds and seedlings, harvesting, processing and other multiple steps, so the accurate identification of factors in TCM production process that may induce the quality risk, as well as reasonable quality control measures are very important. At present, the concept of quality risk is mainly concentrated in the aspects of management and regulations, etc. There is no comprehensive analysis on possible risks in the quality control process of TCM decoction pieces, or analysis summary of effective quality control schemes. A whole process quality control and management system for TCM decoction pieces based on TCM quality tree was proposed in this study. This system effectively combined the process analysis method of TCM quality tree with the quality risk management, and can help managers to make real-time decisions while realizing the whole process quality control of TCM. By providing personalized web interface, this system can realize user-oriented information feedback, and was convenient for users to predict, evaluate and control the quality of TCM. In the application process, the whole process quality control and management system of the TCM decoction pieces can identify the related quality factors such as base environment, cultivation and pieces processing, extend and modify the existing scientific workflow according to their own production conditions, and provide different enterprises with their own quality systems, to achieve the personalized service. As a new quality management model, this paper can provide reference for improving the quality of Chinese medicine production and quality standardization.

[Preparation and characterization of salvianolic acids-tanshinones composite powder for inhalation via co-micronized method].

Salvianolic acids and tanshinones are main hydrophilic and lipophilic extracts from Salvia Miltiorrhiza with significant anti-pulmonary fibrosis effects. The aim of this study was to prepare a co-micronized salvianolic acids-tanshinones composite powder for inhalation using a planetary ball mill. The micronization process parameters were optimized by central composite design (CCD) and response surface methodology (RSM). Treatment time, rotation speed and the ball/sample weight ratio were selected as the independent variables, and the volume fraction of particle size in 1-5 µm was taken as the dependent variable. The powder properties were evaluated by scanning electron microscopy (SEM), laser diffraction and X-ray powder diffraction (XRPD). The powder flow and hygroscopicity were determined with repose angle, compressibility index and critical relative humidity(CRH). According to the results, the salvianolic acids-tanshinones composite powder produced in optimal conditions had a narrow and unimodal particle size distribution and a smaller D50 of 2.33 µm. The volume fraction of particle size in 1-5 µm was 80.82%. The repose angle was (50.60±1.13) °, and the critical relative humidity is about 77%. After being micronized, the particle size significantly reduced, and the number of amorphous substances slightly increased, with no significant changes in powder flow and hygroscopicity. These findings indicate that the grinding method with a planetary ball mill can be used to co-micronize various components with different properties and prepare composite drug powders for dry powder inhalation.

[Advance in studies on long-circulating tumor targeted compound preparations].

Tumor has long been a hard-nut problem in the world medical field. The effect of the conventional drugs is very limited because of the intervention of multiple micro-environmental factors during the occurrence and progression of tumors. With the characteristics of high efficiency, low toxicity and multi-targets synergistic effect, the long-circulating tumor targeted compound preparations show its unique advantages in improving tumor microenvironment and enhancing the therapeutic effect of treatment, thus it has gradually become a hotspot of studies both at home and abroad. Through consulting a great number of professional literatures at home and abroad in recent years, the authors summarized the current studies in vitro and in vive on long-circulating tumor targeted compound preparations in different carriers, in the expectation of providing new ideas and methods for the development of long-circulating tumor targeted compound preparations.

[Optimization and characterization of curcumin-piperine dual drug loaded self-microemulsifying drug delivery system by simplex lattice design].

The objective of the study was to prepare and evaluate the quality of curcumin-piperinedual drug loaded self-microemulsifying drug delivery system(Cur-PIP-SMEDDS). Simplex lattice design was constructed using optimal oil phase, surfactant and co-surfactant concentration as independent variables, and the curcumin and piperine were used as model drugs to optimize Cur-PIP-SMEDDS formulation. In the present study, the drug loadings of curcumin and piperine, mean particle size of Cur-PIP-SMEDDS were made as indicators, and the experiment design, model building and response surface analysis were established using Design Expert 8. 06 software to optimize and verify the composition of SMEDDS formulation. The quality of Cur-PIP-SMEDDS was evaluated by observing the appearance status, transmission electron microscope micrographs and determining particle diameter, electric potential, drug entrapment efficiency and drug loading of it. As a result, the optimal formulation of SMEDDS was CapryoL 90-Cremophor RH40-TranscutoL HP (10:60:30). The appearance of Cur-PIP-SMEDDS remained clarified and transparent, and the microemulsion droplets appeared spherical without aggregation with uniform particle size distribution. The mean size of microemulsion droplet formed from Cur-PIP-SMEDDS was 15.33 nm, the drug loading of SMEDDS for Cur and PIP were 40.90 mg · g(-1) and 0.97 mg · g(-1), respectively, the drug entrapment efficiency were 94.98% and 90.96%, respectively. The results show that Cur-PIP-SMEDDS can increase the solubility and stability of curcumin significantly, in the expectation of enhancing the bioavailability of it. Taken together, these findings can provide the reference to a preferable choice of the Cur formulation and contribute to therapeutic application in clinical research.

[Comparative study on the protein maps of different parts of Cervus nippon antler by two-dimensional electrophoresis].

OBJECTIVE: To optimize the two-dimensional electrophoresis (2-DE) method for the proteome analysis of the Cervus nippon antler, and compare the protein maps of different parts of Cervus nippon antler. METHODS: The total proteins of Cervus nippon antler were extracted by protein lysate containing 7 mol/L Urea, 4% CHAPS, 2 mol/L Thiourea, 65 mmol/L DTT, 1 mmol/L PMSF and 0.2% Bio-Lyte. The proteins were separated by immobilized pH 3 - 10 linear gradient (IPG), 7 cm strips as the first dimension. Isoelectric focusing conditions were optimized. 12% SDS-PAGE was used as the second dimension electrophoresis. The gels were stained with Coomassie brilliant blue and analyzed by PDQuest analysis software. RESULTS: The contents of total protein and the numbers of protein points of three different parts of Cervus nippon antler reduced gradually from the top to the bottom. Comparing three maps of different parts of Cervus nippon antler, there were 18 different protein points. Isoelectric point, molecular weight and gray value of each different protein point were calculated. CONCLUSION: An optimized two-dimensional electrophoresis method for the proteome analysis of the Cervus nippon antler is established. The 2-DE profiles of different parts of Cervus nippon antler exist obvious differences. The different protein points can be used as reference for Cervus nippon antler quality control and evaluation.

Competitive molecular interaction among paeonol-loaded liposomes: differential scanning calorimetry and synchrotron X-ray diffraction studies.

Thermotropic phase behavior of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) liposomes containing 5 mol% cholesterol, or 5 mol% stigmasterol, or 5 mol% paeonol have been investigated by differential scanning calorimetry (DSC) and synchrotron X-ray diffraction (XRD) techniques, to investigate the competitive molecular interaction among paeonol-loaded liposomes. The results show that both sterol and paeonol can incorporate into hydrophobic region and interact with acyl chains of DPPC. Both 5 mol% sterols and 5 mol% paeonol can promote the formation of rippled gel phase of DPPC liposomes at room temperature. 5 mol% paeonol can induce the occurrence of phase separation in DPPC liposomes, but 5 mol% cholesterol or 5 mol% stigmasterol cannot induce this phenomenon. Both the repeat distance and the correlation length of paeonol-poor domain are larger than those of coexisted paeonol-rich domain. Both calorimetric data and SAXS patterns show that sterols have more favorable, stabilizing interactions with DPPC than paeonol, implying that high concentrations of sterols will have a negative effect on the loading of paeonol. In addition, calorimetric data show that cholesterol have a little more favorable, stabilizing interactions with DPPC than stigmasterol. The results of this study will play an important role in optimizing the formulation of paeonol-loaded liposomes.

Absorption mechanism of cyclosporine A loaded pH-sensitive nanoparticles in rats.

CyA was prepared into CyA Eudragit S100 nanoparticles (CyA-S100 NP) and the mechanisms of CyA-S100 NP improving the CyA absorption in gastrointestinal tract (GI) were studied systematically in rats. In the GI distribution study, the emptying rates of CyA-S100 NP in duodenum, jejunum, ileum and colon were all lower than these of Neoral, while in stomach, it was larger than that of Neoral. In in situ recirculating intestine perfusion experiment, the largest absorption in CyA-S100 NP group occurred in ileum while that in Neoral group arised in duodenum. The sequence of (AUC0-240 min)/A for CyA-S100 NP and Neoral group was ileum > duodenum > jejunum > colon and duodenum > jejunum > ileum > colon, respectively. CyA in nanoparticles degradated by luminal contents and subcellular fractions were more slowly than these in Neoral, suggesting the significant protect effect of nanoparticles. Mucoadhesion study in small intestine showed that among all the parts of intestine, CyA-S100 NP exhibited larger mucoadhesive characteristics than Neoral microemulsion. The sequence of mucoadhesion for CyA-S100 NP group was duodenum > ileum > jejunum and colon, while that for Neoral group was duodenum > ileum, jejunum and colon, suggesting different site-specific behaves. These results illustrated that nanoparticles increased the absorption of CyA could be attributed to fast stomach empting rate, absorption site specific, small degradation rate by luminal contents, high bioadhension of nanoparticles to intestine mucosa and the use of P-Glycoprotein inhibitor if there is any. This investigation is helpful for the dosage form design for other peptide or protein drugs.

Long-term studies on the stability and oral bioavailability of cyclosporine A nanoparticle colloid.

The present study was geared at the long-term stability and the changes in oral bioavailability of CyA Eudragit S100 nanoparticles stabilized by suspending agents. CyA Eudragit S100 nanoparticle colloids were prepared by quasi-emulsion solvent diffusion technique and they were mixed with Xanthan gum to obtain suspended nanoparticle colloids. The suspended nanoparticle colloids were preserved at different temperatures for different period of time, as long as 18 months. During the storage period, the CyA concentration, particle size, pH and viscosity were determined. The results indicated that CyA concentration, particle size and viscosity of the colloids had no obvious change. However, the pH increased slightly from 5.5 to about 6.4. The results of bioavailability and pharmacokinetic study revealed that all formulations of nanoparticles showed higher C(max) and higher AUC(0-24) values than that of reference (Neoral). The relative bioavailability of S-CyA-S100 NP initial compared with Neoral was 162.8%. The C(max) and AUC(0-24) values of nanoparticle formulations at 12 and 18 months were both lower than that of the initial. The bioequivalency was suggested between the tested nanoparticle formulations at the initial and 12 months. It was deduced by surface analysis, TEM observation, in vitro release as well as the characteristics of Eudragit S100 that the decrease in bioavailability might be due to the pH change of the nanoparticle colloid.

[Relative bioavailability of cyclosporine A-loaded hydroxypropyl methylcellulose phthalate nanoparticles for oral administration in rats].

AIM: To study the preparation of hydroxypropyl methylcellulose phthalate (HPMCP) nanoparticles and compare its pharmacokinetic characteristics with Neoral. METHODS: HPMCP nanoparticles loaded cyclosporine A were prepared by solvent-nonsolvent method. CyA-HP50 nanoparticles, CyA-HP55 nanoparticles and Neoral were orally administered at the dosage of 15 mg x kg(-1) to rats. The CyA concentration in blood were determined by HPLC. Pharmacokinetic parameters were calculated by 3P97 program. RESULTS: The concentration-time data of the three preparations were best fit by two compartment model. The relative bioavailability of CyA-HP50 and CyA-HP55 nanoparticles calculated by the AUC0-72 were 82.3% and 119.6%, bioequivalent to the reference of Neoral. The relative bioavailability of CyA-HP55 nanoparticles was 145.3% of CyA-HP50 nanoparticles. CONCLUSION: CyA HPMCP nanoparticles could be prepared easily and reproducibly. It was found that the oral absorption of CyA can be increased by using the HPMCP nanoparticles.

[Influence of suspending agents on relative bioavailability of cyclosporine A-loaded HPMCP nanoparticles for oral administration to rats].

OBJECTIVE: To study the influence of suspending agents on the relative bioavailability of Cyclosporine A-loaded HPMCP(HP55) nanoparticles for oral administration. METHODS: Suspending agents such as Vanzan, HPMC, Carbopol were added into cyclosporine A-loaded HP55 nanoparticles. The suspended nanoparticle formulations and Neoral were administered orally in a dosage of 15 mg/kg to rats. The CyA concentrations in the blood sample were determined by HPLC. Pharmacokinetic parameters were calculated by 3P97. RESULTS: The concentration-time data of these preparations were best fit by two compartment model with a weight of 1/C(2). Compared with the reference Neoral microemulsion, the relative bioavailability of 2 g/L Carbopol, 5 g/L Vanzan, 8, 5, 3 g/L HPMC suspended nanoparticles were 70.2%, 84.3%, 90.0%, 94.5% and 97.7%, respectively. Their viscosity values were 550, 362, 105, 30 and 15 mPaxs, respectively. CONCLUSION: With the increase in viscosity, the relative bioavailability of nanoparticle formulations decreased. So, it is important to select the appropriate viscosity of suspending agents in the formulation design.

Bioavailability and pharmacokinetics of cyclosporine A-loaded pH-sensitive nanoparticles for oral administration.

The pH-sensitive cyclosporine A (CyA) nanoparticles were prepared by the solvent displacement method with enteric dissolved polymer of hydroxypropyl methylcellulose phthalate (HPMCP; including HP50 and HP55). The CyA nanoparticles were analyzed by HPLC for yield and encapsulation efficiency, dynamic light scattering for particle size and transmission electron microscopy (TEM) for morphology. The bioavailability of CyA-HP50 and CyA-HP55 nanoparticle colloids were evaluated in rats, compared with the current available CyA microemulsion (Neoral). The bioavailability of CyA-HP55 nanoparticle colloids with various suspending agents was also investigated. The results obtained demonstrated that the pH-sensitive CyA nanoparticles with a particle size of 50-60 nm and encapsulation efficiency over 95% could be reproducibly prepared. The bioavailability of CyA-HP50 and CyA-HP55 nanoparticle colloids calculated by the AUC(0-72) were 82.3% and 119.6%, similar to the reference of Neoral, while the bioavailability of CyA-HP55 nanoparticle colloids was found to be higher than that of CyA-HP50 nanoparticle colloids. The increase of mean residence time (MRT) and the decrease of elimination constant of the central compartment (K10) for both CyA-HP50 and CyA-HP55 nanoparticle colloids compared with the reference indicated significant sustained release of CyA from the nanoparticles. The effects of the suspending agents on the bioavailability of CyA-HP55 nanoparticles were observed, and the bioavailability decreased as the concentration of suspending agents or the viscosity of the nanoparticle colloids increased.

[Preparation of cyclosporine A pH sensitive nanoparticles and oral pharmacokinetics in rats].

AIM: To study the preparation conditions and its oral pharmacokinetic characteristics of cyclosporine A (CyA) pH sensitive nanoparticles. METHODS: The CyA pH sensitive nanoparticles were prepared by the quasi-emulsion solvent diffusion technique (QESD). Male Sprague-Dawley (SD) rats weighing (250 +/- 20) g were selected and randomly divided into five groups. The bioavailability of CyA from nanoparticles and Neoral microemulsion were assessed at a dose of 15 mg x kg(-1) by gavage. The concentration of CyA in whole blood samples was detected by HPLC to evaluate the relative bioavailability of CyA pH sensitive nanoparticles. RESULTS: The blood concentration profiles of CyA pH sensitive nanoparticles in rats fitted to two compartment models using 3P87 pharmacokinetic calculation program. Compared with the Neoral microemulsion, the relative bioavailability of CyA was 94.8%, 115.2%, 113.6% and 132.5% for CyA-E100, CyA-L100, CyA-L100-55 and CyA-S100 nanoparticles respectively. CONCLUSION: CyA-S100 nanoparticles was shown to significantly improve the oral bioavailability of CyA compared with Neoral microemulsion (P < 0.05). While there were no significant differences between Neoral microemulsion and other CyA pH sensitive nanoparticles. With these results, the potential of pH-sensitive nanoparticles for the oral delivery of CyA was confirmed. Furthermore, this formulation approach can be used to improve the oral bioavailability of other poorly soluble and poorly absorbable drugs.