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OBJECTIVE To optimize the extraction process of Sarcandra glabra. METHODS The contents of rosmarinic acid and isofraxidin in S. glabra were determined by HPLC； ultrasonic time， ultrasonic temperature， solid-liquid ratio （mL/g） and methanol volume fraction were investigated by single factor test. Based on the results of single factor test， experimental scheme was designed by Box-Behnken response surface method， and the entropy weight method was used to assign the weight of each index and calculate the comprehensive score. Taking the comprehensive score as the evaluation index， the extraction process of S. glabra was optimized， and then optimized extraction process was verified. RESULTS The optimal extraction technology of S. glabra included ultrasonic time of 40 min， ultrasonic temperature of 45 ℃， liquid-solid ratio of 50∶1， methanol volume fraction of 70%. The results of 3 times of verification experiment showed that average comprehensive score was 0.988 6， and the RSD was 0.50%. The deviation between the actual value and the predicted value （0.985 1） of each comprehensive score was within ±1%. CONCLUSIONS The optimized extraction method is stable， feasible and repeatable， which can provide reference for extraction of S. glabra.
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OBJECTIVE To optimize the water extraction process of Maxing kechuan granules. METHODS With the contents of ephedrine hydrochloride， bergenin， prim-O-glucosylcimifugin， 5-O-methylvisamin， naringin and hesperidin and the rate of extraction as the evaluation indexes， the weight was determined by the analytic hierarchy process（APH）-entropy weight method， and the comprehensive score was calculated as the response value. Based on the single-factor test， the Box-Behnken response surface method was used to investigate the factors， and the best water extraction process of Maxing kechuan granules was optimized； process validation was also carried out. RESULTS The best water extraction process of Maxing kechuan granules optimized was as follows： soaking for 40 minutes， adding 8 times water， and extracting for 180 minutes. After three validation tests， the comprehensive score was 94.82 （RSD＝0.96%， n＝3）， which had a small difference from the predicted value of 94.64. CONCLUSIONS The water extraction process of Maxing kechuan granules is stable and reliable， which can provide a reference for the development of the preparation.
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OBJECTIVE To optimize the extraction process of polysaccharides from Dendrobium officinale， and preliminarily study its effect on acute lung injury （ALI） in mice. METHODS Using D. officinale as raw material， the polysaccharides were extracted from D. officinale by ultrasonic-assisted hot water immersion. Using the extraction rate of D. officinale polysaccharides as response value， the single-factor experiments and Box-Behnken response surface method were used to optimize the ratio of material to liquid， extraction time and extraction temperature. ALI mice were induced by lipopolysaccharide. Using prednisone acetate （5 mg/kg） as the positive control， the effects on the mass ratio of wet and dry lung and pathological changes of lung tissue （HE staining and Masson staining） of low-dose， medium-dose and high-dose D. officinale polysaccharides （50，100，200 mg/kg） were investigated. RESULTS The optimal extraction technology of D. officinale polysaccharides was as follows： the ratio of material to liquid was 1∶25 （g/mL）， the extracting time was 1 h， and the extracting temperature was 58 ℃ . Under these conditions， the average extraction rate of D. officinale polysaccharides was 37.75% （RSD＝1.12%，n＝3）， the relative error of which with predicted value （38.63%） was 2.28%. Compared with the model group， the ratios of wet and dry lung in the positive control group and D. officinale polysaccharides groups were all decreased significantly （P＜0.05 or P＜0.01）， and the pathological changes in lung tissue （severe destruction of alveolar structure， significant widening of alveolar septa， extensive infiltration of inflammatory cells and proliferation of fibroblasts） were alleviated to varying degrees. CONCLUSIONS The optimal extraction process of D. officinale polysaccharides is feasible； the obtained polysaccharide extract has a certain improvement effect on ALI in mice.
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OBJECTIVE：To optimize the honey-stir-fried technology of Chelidonium majus . METHODS ：Taking the mass ratio of water to honey ，the ratio of honey water to C. majus ，stir-fired temperature ，stir-fired time as the factors ，the total contents of chelidonine ，coptisine hydrochloride ，sanguinarine，berberine，chelerythrine as response values ，Box-Behnken response surface method was used to optimize the processing technology ，and valifation test was conducted. RESULTS ：The optimum process conditions were as follows the ratio of water to refined honey 1∶1.9（g/g），the ratio of honey water to C. majus 21∶100（g/g）， stir-fried temperature 122 ℃，stir-fried time 10.40 min. After 3 times of validation ，average total contents of 5 components was 10.37 mg/g（RSD＝0.23％），relative error of which with predicted value （10.39 mg/g）was 0.19％. CONCLUSIONS ：The optimized honey-stir-fried technology of C. majus is stable and feasible.
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Objective: To optimize the extraction process parameters of Guizhi Shaoyao Zhimu Granules (GSZG). Methods: Using high performance liquid chromatography and Elisa, the extraction rate of trans-cinnamaldehyde, paeoniflorin, mangiferin, glycyrrhizic acid, the dry extract yield of extracted herbs and inflammatory factor IL-6 were comprehensively evaluated. The information entropy weighting method was used to determine the objective weight of each index, and response surface methodology was adopted to optimize the extraction process parameters of GSZG. Results: The method had good linear relationship within the range of 3.27-104.64 μg/mL for trans-cinnamaldehyde (r = 0.999 9), 8.16-261.03 μg/mL for paeoniflorin (r = 1.000 0), 1.39-89.27 μg/mL for mangiferin (r = 0.999 9), and 1.00-33.00 μg/mL for glycyrrhizic acid ammonium salt (r = 0.999 9). Guizhi-Shaoyao-Zhimu extraction had the effect of inhibiting the proliferation of MH7A cells (molded by TNF-α) with IC50 of 1.02 mg/mL, and had anti-inflammatory activity. Entropy method was more scientific, reasonable and stable. According to the comprehensive scoring results and practical situation, it was determined that the best extraction process of the preparation was to add 16 times the amount of water, and decocted three times for 1 h each time. The RSD of the predicted value was less than 3% compared with the measured value. Conclusion: The preferred process has high extraction rate, with good stability and repeatability, which is suitable for the mass production of GSZG.
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Objective: To optimize the prescription and preparation process of "Hugan I" Orally Disintegrating Tablets, and investigate its efficacy against acute liver injury in mice. Methods: Single factor method was used for disintegrants, lubricants, and fillers screening. Taking the appearance, hardness, friability and disintegration time of the tablets as the comprehensive evaluation index, the dosage of disintegrant, micro-silica gel and magnesium stearate was selected as the investigation factor. The Box-Behnken response surface method was used to optimize the orally disintegrating tablets. Acetaminophen (APAP, 500 mg/kg) was used to replicate acute liver injury model by one-time high-dose intragastric administration to investigate the effects of orally disintegrating tablets on the activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum, the content of glutathione (GSH) and malondialdehyde (MDA) and morphological changes in liver tissue. Results: The optimal prescription was as following: dry paste powder 22.00%, microcrystalline cellulose 18.00%, sorbitol 20.00%, mannitol 16.00%, Aspartame 0.50%, citric acid 0.50%, disintegration agent L-HPC 20.00%, micro-powder silica gel 2.50% and magnesium stearate 0.50%. The hardness of the orally disintegrating tablets was 4-7 kg, the mean disintegration time was about 50 s, and the mean friability was around 0.85%. Compared with the model group, there were significant differences (P < 0.01) in Biphenyl diester control group, "Hugan I" Decoction group and "Hugan I" Orally Disintegrating Tablets group, and the levels of ALT and AST in the serum of the mice were significantly decreased, The content of MDA in the liver tissue was decreased, which improved the damage of APAP to liver tissue. Conclusion: The formulation of the "Hugan I" Orally Disintegrating Tablet is feasible and easy to operate, which achieves the same effect with "Hugan I" Decoction that effectively prevent liver damage caused by acetaminophen with no significant differences.
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OBJECTIVE：To optimi ze the ratio of four comp onents of Compound renshen jianti formulation （Panax ginseng ， Dioscorea oppositifolia ，Lycium barbarum fruit，Alpinia oxyphylla ），and to investigate its anti-fatigue activity and acute toxicity. METHODS：The water extract of Compound renshen jianti formulation was prepared by water extraction ，concentration and decompression drying. By single factor tests ，using weight-bearing swimming time as index ，the effects of four factors were investigated，such as the amount of P. ginseng ，D. oppositifolia ，L. barbarum fruit，A. oxyphylla . On the basis of single factor tests，using comprehensive score of weight-bearing swimming time ，serum urea nitrogen content ，liver glycogen content and AUC of blood lactate after exercise as index ，the formulation was optimized by Box-Behnken response surface method. The mice was divided into blank control group （water），positive control group （Renshen hongjingtian capsules ，0.135 g/kg）and compound low-dose，medium-dose and high-dose groups [the optimal ratio of Compound renshen jianti formulation extract （called“optimal compound formulation ”for short ）4.08，8.16，12.24 g/kg，by crude drug] ，intragastric administration of drug or distilled water 20 mL/kg，once a day ，for consecutive 30 d. The weight-bearing swimming time ，the contents of serum urea nitrogen ，liver glycogen and blood lactate AUC after exercise were used to optimize its anti-fatigue activity of optimal compound formulation. The comprehensive score was calculated based on the measured data of mice in the compound formulation middle-dose group ， and the difference between it and the theoretical prediction value was compared. The mice were given optimal compound formulation intragastrically （total dose 16.00 g/kg， by extract）. The general state ， body mass change ， toxic characteristics and death of mice were observed and recorded for 14 days. Median lethal dose （LD50）and maximum tolerated dose （MTD）were measured. RESULTS ：The optimal formulation ratio of Compound renshen jianti formulation included that P. ginseng 1.5 g，D. oppositifolia 10 g，L. barbarum fruit 10 g，A. oxyphylla 3 g. Results of anti-fatigue activity validation test showed that the optimal compound formulation could significantly prolonged weight-bearing swimming time ，reduced serum content of urea nitrogen ，blood lactate content and its AUC （except for low-dose group ），while significantly increased the content of liver glycogen （P＜0.05 or P＜0.01）. Average comprehensive score of medium-dose group was 96.95，which was only 0.06％ different from the theoretical prediction value of 97.01. The results of acute toxicity test showed that there was no death in mice. The oral MTD of the optimal compound formulation was more than 15 g/kg，which was non-toxic. CONCLUSIONS ：The optimal Compound renshen jianti formulation has effective anti-fatigue activity of mice ，and has no significant toxic effect.
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Objective: The optimum extraction process parameters of Cistanche deserticola were selected to study the effects of different drying methods on five phenylethanoid glycosides. Methods: Single factor screening combined with Box-Behnken response surface method was used to optimize the extraction process. After optimal conditions were extracted, HPLC method was used to detect the content of echinacoside, cistanche A, verbascoside, isoacteoside, and 2’-acetylacteoside in different drying methods, and one-way ANOVA, cluster analysis, principal component analysis and close value analysis were used to analyze the content of five phenylethanoid glycosides to choose the best drying method. Results: Optimal extraction process was as following: methanol volume fraction was 55.14%, liquid to material ratio was 46.39, extraction time was 38.50 min. Cluster analysis, principal component analysis, and close value analysis showed that the quality of C. deserticola obtained by freeze-drying method was the best, followed by drying at 80 ℃ and the lowest at 40 ℃. Conclusion: Using this process to extract C. deserticola, the five phenylethanoid glycosides are completely and fully extracted. Although the freeze-drying method of C. deserticola has the highest active ingredient retention, from the production point of view, the 80 ℃ drying method can achieve a balance of cost and efficiency.
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Objective: To prepare pegylated long-circulating liposomes co-encapsulated by costunolide (Cos) and dehydrocostus lactone (DL), optimize the formulation and process, and evaluate the quality. Methods: The pegylated long-circulating liposomes co-encapsulated by Cos and DL were prepared by film hydration method. Single factor test and Box-Behnken response surface methodology were used to optimize the preparation process with encapsulation efficiency of Cos and DL as the index. The particle size, surface potential, encapsulation efficiency and in vitro release of the liposomes were evaluated. Results: The optimal preparation conditions were as follows: drug-to-lipid ratio was 0.14, ratio of cholesterol to phospholipid was 0.05, mPEG-2000-DSPE addition amount was 6%, hydration time was 30 min, and probe ultrasonic time was 4 min. The obtained liposome was round and uniform in distribution, with an average particle size of (104.8 ± 2.48) nm, a polydispersity index (PDI) of (0.245 ± 0.031), and a Zeta potential of (-9.7 ± 0.23) mV, the encapsulation efficiency of Cos and DL were (91.9 ± 2.6)% and (94.41 ± 1.23)%, respectively. Conclusion: The PEGylated long-circulating liposome prepared by the process and prescription optimization has good appearance and high encapsulation efficiency, which can meet the application requirements.
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OBJECTIVE： To optimize the water extraction technology of Chaihu anxin capsules. METHODS： Taking comprehensive scoring value of the contents of gallic acid，chlorogenic acid，puerarin，glycoside，rutin，cinnamic acid， quercetin and the yield of extract as investigation index， using multiple of adding liquid， soaking time， reflux time and extraction times as factors， water extraction technology of Chaihu anxin capsule was optimized by Box-Behnken response surface method based on single factor test. Validation test was conducted. RESULTS： The optimal extraction technology of Chaihu anxin capsules was adding 11 times of water， soaking for 10 h， extracting for 2 times， refluxing for 1.5 h each time. In validation test， the relative deviation of comprehensive scoring value to predicted value was 1.87％ for 3 batches of samples （RSD＜2％， n＝3）. CONCLUSIONS： The optimal extraction technology is simple， stable and suitable for further production of Chaihu anxin capsules.
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OBJECTIVE: To optimize the formulation of Fe3O4 nanoparticles modified with polyethylene glycol (PEG)through Box-Behnken response surface method.To investigate its release properties in vitro to provide references for the study of drug delivery system. METHODS: Firstly, the formulationof Fe3O4 nanoparticles was optimized by Box-Behnken response surface method. Secondly, the physical and chemical stabilities of Fe3O4 nanoparticles were determined at different stages. Next, doxorubicin hydrochloride, scutellarin and 5-fluorouracil were respectively loaded into Fe3O4 nanoparticles by ultrasonic stirring method and the drug release ability of Fe3O4 nanoparticles was studied by dialysis method. Finally, different mathematical models were applied to fit the release data to explain the release mechanism, and the release ability of Fe3O4 nanoparticles was investigated at different temperatures to clarify the effect of photothermal effect on drug release. RESULTS The particle size of Fe3O4 nanoparticles was from 20 to 30 nm at room temperature. Fe3O4 nanoparticles loading with water-soluble drugs 5-fluorouracil was incompatible with the five models. However, when doxorubicin hydrochloride was loaded, its release fitted well with the Higuchi equation. And both zero-order equation and the Hixson-Crowell equation can match well with such Fe3O4 nanoparticles loading with scutellarin. Finally, it can be clarified with mechanism-verified Ritger-Peppas equation that the simple diffusion motivated the drug release of Fe3O4 nanoparticles loaded with hydrophilic drugs, and the Zero dissolution release mechanism worked when loaded with hydrophobic drugs.As the temperature increases, the release ability of Fe3O4 nanoparticles was increases. CONCLUSION: Hydrophobic drugs can be loaded with SCU in the Fe3O4 nanoparticles by ultrasonic stirring method to improve the biocompatibility of the drugs, which provide some experimental foundation for the research and development of new formulations of poorly soluble drugs.
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Objective:To optimize the decoction process of Xiaochengqi decoction by Box-Behnken response surface method. Methods:Rhein,aloe-emodin and synephrine were chosen as the evaluation indices. After the material-liquid ratio, decocting frequency and decocting time were studied,Box-Behnken response surface method was used to optimize the three factors using the weighted calculation value of the extraction rate of above indicator components. Results:The best conditions were as follows:the material-liquid ratio was 1:10,the decocting frequency was 3,and the decocting time was 1.0 h. The deviation of measured value and predicted value was 1.15%. Conclusion:The best decocting conditions are promising and reliable.
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Objective:To optimize the high pressure steaming processing technology for Polygonum multiflorum Thunb.by Box-Behnken response surface methodology , and compare with the traditional processing .Methods:The effects of factors such as steaming temperature, steaming time and drying temperature on polysaccharide content , stilbene glucoside content and normalized value in Po-lygonum multiflorumThunb.were studied by Box-Behnken response surface methodology .The content differences of polysaccharides and stilbene glucoside between the high pressure steaming processed product and the traditional processed product were evaluated .Re-sul ts:The best high pressure steaming processing conditions for Poyl gonumm luitlfo urm Thunb .were as follows:the steaming tempera -ture was 1254.℃ , the steaming time was3.1 h, and the drying temperature was 52℃.The contents of polysaccharides and stilbene glycosides in Polygonum multiflorum Thunb.processed by the high pressure steaming method were 1.24-fold and 5.26-fold higher than those processed by the traditional method .Conclusion:Box-Behnken response surface method can be used to optimize the high pres-sure steaming processing for Polygonum multiflorum Thunb., and the method is simple and predictable .
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Objective To optimize the preparation technology for Centella asiatica total glucosides (CTG) liposome and to investigate its percutaneous permeability in vitro. Methods Liposomes were prepared by reverse-phase evaporation technique. Taking the entrapment efficiency of madecassoside and asiaticoside as indexes, the preparation of liposome was optimized by using single factor and Box-Behnken response surface method. The properties of liposomes including morphology, entrapment efficiency, mean diameter, Zeta potential, and accumulative release were studied. Results The optimal formulation was lecithin-cholesterol (4:1), lecithin-CTG (23.22:1), and organic- aqueous (7:1). The liposome was smooth and spherieal in appearance, mean diameter, and Zeta potential were 201.7 nm and -15.7 mV, respectively. The entrapment efficiency of madecassoside and asiaticoside were 75.85% and 84.94%. The in vitro 12 h accumulative release was 52.10% and 45.97%. The equations for the permeation rate of madecassoside and asiaticoside in liposomes were Q = 67.93 t1/2-50.34, R2 = 0.988, Q = 139.74 t1/2-241.2, R2 = 0.987, respectively. The retention amount in the skin was 76 μg/cm2 and 48.7 μg/cm2, which were 1.56 and 1.18 times higher than those of solution. Conclusion The optimized process is rational, feasible, and good stability. The CTG liposome prepared in this study have the smaller size, the higher encapsulation efficiency, higher retain in skin and obvious sustained-release effects.
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Objective: To prepare ibuprofen sustained-release dropping pills, to evaluate the accumulative release percentage in vitro and to study the drug state in the base.Methods: With the drug content, mass ratio of water-soluble base to insoluble base and mass ratio of stearic acid to glyceryl monostearate as the investigation factors, and the comprehensive score of 2-hour and 10-hour cumulative dissolution rate as the evaluation index, a Box-Behnken response-surface method was used to screen the optimal formula of ibuprofen sustained-release dropping pills.The drug state in the matrix was examined by differential scanning calorimetry (DSC).Results: The optimal formula of ibuprofen sustained-release dropping pills was as follows: the drug content of 10%, water-soluble and insoluble matrix ratio of 4∶1, and stearic acid and glyceryl monostearate ratio of 3∶1.The maximum cumulative dissolution rate of ibuprofen sustained-release dropping pills was 78.85%.The DSC analysis showed that the drug crystallization peak disappeared in the sustained-release dropping pills, and formed a solid dispersion.Conclusion: The preparation has good sustained-release effect, and the preparation process is simple.
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OBJECTIVE:To optimize the formulation of Cilnidipine sustained-release tablet,and study its drug-release mecha-nism. METHODS:Solvent method was adopted to prepare the cilnidipine solid dispersion,then Cilnidipine sustained-release tablet was prepared by using hypromellose K4M(HPMC K4M)as release material. Using comprehensive scores of cumulative release de-gree in 2,6,12 h as indexes,single factor method and Box-Behnken response surface method were used to screen the amounts of HPMC K4M and ethyl cellulose (EC),lactose-microcrystalline cellulose (MCC) ratio in formulation of Cilnidipine sustained-re-lease tablet,and verification test was conducted. The drug-release mechanism of Cilnidipine sustained-release tablet was investigat-ed by model fitting way. RESULTS:The optimal formulation was as follow as 25％ of cilnidipine solid dispersion,30％ of HPMC K4M,10％ of EC,lactose-MCC ratio of 1:1(m/m). The adhesive was 5％ PVPP ethanol solution and the lubricant was 0.5％magnesium stearate. The cumulative release degrees of prepared sustained-release tablet in 2,6,12 h were(21.4±3.3)％,(62.9± 2.8)％,(85.4±0.5)％(n=3),relative error of which to predicted value 25％,60％,90％were 14.4％,4.8％and 5.1％. Release curve showed the highest fitting degree with the first-order release model,conforming to non-Fick diffusion. CONCLUSIONS:Cil-nidipine sustained-release tablet with sustained-release effect is successfully prepared by optimized formulation.
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Objective To optimize the color conditions of spectrophotometric determination of total saponins in Fructus Trichosanthis. Methods Several factors affecting the content determination of total saponins in Fructus Trichosanthis were studied , including the color temperature,color time,5%vanillin-acetic acid dosage,as well as the amount of perchloric acid. The analysis con-ditions were optimized by Box-Behnken response surface method. Results The optimized conditions were:temperature 60℃,the col-or time 25 min,5%vanillin-acetic acid 0.1 ml and perchloric 0.6 ml. The color was stable and the determination results were accurate. Conclusion The color conditions determined by Box-Behnken response surface method can be used for content determination of total saponins in Fructus Trichosanthis.
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OBJECTIVE:To optimize the extraction technology of garlic oil. METHODS:Using extraction rate of garlic oil as index,based on single factor test,Box-Behnken response surface method was used to optimize conditions of steam distillation method for the extraction of garlic as fermentation time,solid to liquid ratio,fermentation temperature and the verification test were made for the optimized technology. RESULTS:The optimal extraction technology was as follows as fermentation time of 4.5 h,solid to liquid ratio of 1:7,fermentation temperature of 55 ℃. The average extraction rate of garlic oil in verification test was 0.32%(RSD=1.43%,n=3);the relative error between the measured value and predicted value was 0.06%. CONCLUSIONS:Box-Behnken response surface method is simple,reasonable and feasible to optimize the extraction technology of garlic oil,which can provide a scientific basis for industrial production.
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Objective To optimize the color conditions of spectrophotometric determination of total saponins in Fructus Trichosanthis. Methods Several factors affecting the content determination of total saponins in Fructus Trichosanthis were studied, including the color temperature, color time, 5% vanillin-acetic acid dosage, as well as the amount of perchloric acid. The analysis conditions were optimized by Box-Behnken response surface method. Results The optimized conditions were: temperature 60°C, the col or time 25 min, 5% vanillin-acetic acid 0.1 ml and perchloric 0.6 ml. The color was stable and the determination results were accurate. Conclusion The color conditions determined by Box-Behnken response surface method can be used for content determination of total saponins in Fructus Trichosanthis.
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Objective:To optimize the extraction process of Ilex chinensis Sims by Box-Behnken response surface method. Meth-ods:The HPLC determination of pedunculoside was performed and validated. With the extraction rate of pedunculoside as the index, the influencing factors including material-liquid ratio, ethanol concentration, reflowing temperature and decocting frequency were opti-mized by Box-Behnken response surface method. Results:The optimized parameters were as follows:the material/liquid ratio was 1:10, the ethanol concentration was 70%, the ultrasonic temperature was 80℃,and the decocting frequency was three times. Conclu-sion:The HPLC method and the best extraction conditions are reliable.