Optimization of extraction process for classic prescription Yihuang Decoction based on Box-Behnken design-response surface methodology, standard relation, and analytic hierarchy process combined with entropy weight method / 中国中药杂志

Based on the concept of quality by design(QbD), the Box-Behnken design-response surface methodology combined with standard relation(SR) and analytic hierarchy process(AHP)-entropy weight method(EWM) was applied to optimize the extraction process of the classic prescription Yihuang Decoction. The content of geniposidic acid, phellodendrine hydrochloride, and berberine hydrochloride in Yihuang Decoction, the extract yield, and fingerprint similarity were used as the critical quality attributes(CQAs) of the extraction process. The extraction time, water addition, and extraction times were used as the critical process parameters(CPPs). After determining the levels of each factor and level through single-factor experiments, response surface experiments were designed according to the Box-Behnken principle, and the experimental results were analyzed. The SR between each sample and the reference sample under various evaluation indicators of different extraction parameters was calculated. The weights of the five evaluation indicators were determined using AHP-EWM, followed by comprehensive evaluation. A function model between CPPs and CQAs characterized by comprehensive scores was established to predict the optimal extraction process parameters. In the final comprehensive weight coefficients, the yield rate accounted for 43.1%, and the content of berberine hydrochloride, phellodendrine hydrochloride, and geniposidic acid accounted for 35.1%, 6.3%, and 15.5%, respectively. After comprehensive score analysis with SR, the established second-order polynomial model was statistically significant(P<0.01, and the lack of fit was not significant). The predicted optimal extraction conditions for Yihuang Decoction were determined as follows: 8-fold volume of water, extraction time of 1.5 h, and extraction once. The mean comprehensive score of the validation experiment was 85.77, with an RSD of 0.99%, and it met the quality control stan-dards for the reference sample of Yihuang Decoction. The results indicate that the optimized extraction process for Yihuang Decoction is stable and reliable, and the water extract is close in quality attributes to the reference sample. This can serve as a foundation for the research and development of granules in the future. Box-Behnken design-response surface methodology combined with SR and AHP-EWM can provide references for the modern extraction process research of other classic prescriptions.

Optimization of preparation technology of baicalin lipid nano foam aerosol / 中国药房

OBJECTIVE To optimize the pr eparation technology of the baicalin lipid nano foam aerosol （BC-LN-FA）. METHODS Baicalin lipid nanoparticle （BC-LN）and BC-LN-FA were prepared by the thin film dispersion method and homogeneous emulsification method ，respectively，using baicalin （BC） as the model drug. The preparation technology was optimized by Box-Behnken design-response surface methodology using particle size and encapsulation efficiency （EE）as indexes ，with dosage ， emulsifier dosage ，co-emulsifier dosage and homogenization time as factors. The morphology ，particle size ，polymerdispersity index（PDI），EE，the viscosity ，the foam dissolution rate and in vitro transdermal release of BC-LN-FA were characterized. RESULTS The optimal technology included 25 mg BC ，40 mg emulsifier （mass ratio of stearic acid-soybean lecithin-glycerol was 1∶1∶1），30 mg co-emulsifier （mass ratio of octadecanol-lactic acid was 1∶1），homogenization time of 20 min. Results of 3 times of validation tests showed that particle size of prepared BC-LN-FA was （151.70±2.40）nm，EE was （68.62±1.16）％；the deviation of them from the predicted value （particle size of 150.80 nm，EE of 67.02％）were 0.60％ and 2.39％ respectively. The BC-LN-FA prepared by the optimal process was light yellow opalescence ，uniform in particle size and round-like in shape. The viscosity，the foam dissolution rate ，the content of BC and PDI were （122.92±5.09）mPa·s，（65.32±3.22）％，（7.01±0.12）％ and（0.199±0.006），respectively. At 48 h，the cumulative release rates of BC-LN-FA in phosphate buffer saline （PBS）at pH 7.4， 6.8，5.0 were（54.12±2.69）％，（57.85±4.25）％ and（59.47±1.83）％，respectively；those of free BC in PBS at pH 7.4 was only （15.04±1.43）％. CONCLUSIONS The optimized technology is stable and feasible. Prepared BC-LN-FA has a uniform particle size，high digestion rate and certain viscosity.

Formulation Optimization and Characterization of Docetaxel PELGE Nanoparticles and Preliminarily Evaluation of Its Drug Release and Antitumor Activity in vitro / 中国药房

OBJECTIVE：To optimize the f ormulation of docetaxel （DTX）-mPEG-PLGA-mPEG （PELGE）-nanoparticles （NPs），and to characterize it and evaluate its in vitro drug release and antitumor activity. METHODS ：PELGE were synthesized by ring-opening polymerization. DTX-PELGE-NPs were prepared by using emulsion solvent evaporation method. The content of DTX in DTX-PELGE-NPs was determined by HPLC. Box-Behnken design-response surface methodology was applied to optimize the formulation of the nanoparticles using the amount of DTX ，PELGE and poloxamer 188 as independent variable ，using entrapped efficiency as dependent variable. The particle size and Zeta-potential of DTX-PELGE-NPs were characterized by laser particle size analyzer and transmission electron microscope. The in vitro release of the DTX-PELGE-NPs was investigated by ultra-filtered centrifugation，using DTX injection as reference. In vitro cytotoxicity of the DTX-PELGE-NPs was investigated by MTT assay ， using DTX and PELGE-NPs without DTX as reference . RESULTS ：The optimal formulation included 2.80 mg DTX ，20.60 mg PELGE and 6％ poloxamer 188. The entrapped efficiency of optimized DTX-PELGE-NPs was （86.79±1.32）％；drug-loading amount was （10.21±0.78）％，and average particle size was （78.4±2.9）nm；polydispersity coeffici ent was （0.187±0.018）and Zeta potential was （－20.6±1.5）mV. Furthermore ，DTX- PELGE-NPs showed a regular spherical and uniform distribution under scanning electron microscopy. Compared with DTXinjection（accumulative release rate of 92.3％ at 4 h），DTX- PELGE-NPs had a significant sustained-release effect （accumu-lative release rate of 78.6％ at 36 h）. 0.1-50 μg/mL PELGE-NPs had no obvious cytotoxicity to human breast cancer cells MCF-7（P＞0.05）. 0.5-10 μg/mL DTX-PELGE-NPs could significantly inhibit the growth of human breast cancer cells MCF-7， and its inhibitory effect （except for DTX-PELGE-NPs 10 μg/mL group）was significantly stronger than that of DTX injection （P＜ 0.05）. CONCLUSIONS ：The optimized formulation is stable and feasible. The obtained DTX-PELGE-NPs not only have uniform particle size ，high encapsulation rate obvious slow-release effect ，but also have stronger anti-tumor effect in vitro than DTX injection.

Optimization of Extraction Process of Thymol and Carvacrol in Origanum vulgare by Box-Behnken Design-Response Surface Methodology / 中国药学杂志

OBJECTIVE: To optimize the extraction process of thymol and carvacrol in Origanum vulgare by Box-Behnken design-response surface methodology. METHODS: On the basis of single factor experiment, taking the sum of extraction rates of thymol and carvicol as the evaluation index, Box-Behnken design was used to investigate the effects of ethanol concentration, liquid-solid ratio and medicinal powder on the extraction rate. RESULTS: The optimal extraction parameters were as follows: ethanol concentration was 80%, liquid to solid ratio was 13∶1 (mL/g), medicinal powder passing through 40 meshes was used, and the highest extraction rate was 694.80 μg•g-1, with a small deviation from the predicted value. CONCLUSION: The optimal extraction method is simple, with low cost and good predictivity, and it can provide experimental basis for further large-scale production of thymol and carvacrol in Origanum vulgare.

Optimization of processing technology of Momordicae Semen cream by Box- Behnken design-response surface methodology / 中草药

Objective To optimize the optimum processing technology of Momordicae Semen cream using Box-Behnken design-response surface method (BBD-RSM). Methods The overall desirability (OD) of indexes of the content of 3-O-β-D- glucuronic acid methyl ester, β-sitosterol, and oleanolic acid and the content of fatty oil in gypsogenin was comprehensively evaluated, and BBD-RSM with three factors and three levels was used to study the effect of baking temperature and time, and pressing time on the processing technology of Momordicae Semen cream. Results According to the experiment, the optimum processing conditions were optimized: the baking time 1.68 h, the baking temperature 80 ℃, the pressing time 30 min, and the OD value was 0.777. Considering the actual situation, the optimum processing technology of Momordicae Semen was obtained by fine-tuning the baking time (A). That was, the baking time was 1.7 h, the baking temperature was 80 ℃, and the pressing time was 30 min. Also, the calculated OD values were 0.779, 0.783, 0.766, and its RSD was 1.15% through the obtained conditions in parallel with three batches of samples. Conclusion The processing technology optimized by Box-Behnken design-response surface method has the advantages of stable, good model prediction effect and a new processing technology for Momordicae Semen cream production.

Optimization of Extraction Process for Active Ingredients in Seeds of Sophora alopecuroides by Plackett-Burman Design and Response Surface Analysis / 中国药学杂志

OBJECTIVE: To optimize extraction process for active ingredients in seeds of Sophora alopecuroides, to provide a reference for scale production. METHODS: Active ingredients from Sophora alopecuroides were extracted by ethanol, with average yield of oxysophocarpine and oxymatrine as index, some factors affecting index were firstly evaluated by Plackett-Burman design, then taking oxysophocarpine and oxymatrine as indexes respectively, extraction conditions were optimized by Box-Behnken design, experimental data was fitted by multiple linear regression and binomial formula fitting, extraction process was optimized by response surface method, and prediction was carried out through comparing the observed and predicted value. RESULTS: Extracting times, crushing degree and solvent times had significant effects on yields of oxysophocarpine and oxymatrine; binomial equation fitted well with good predictability. optimum extraction technology of Sophora alopecuroides was as following:crushed through 65 mesh sieve, extracted 4 times with 12-fold the amount of 60% ethanol for 2 h each time; yield of oxysophocarpine and oxymatrine was 92.3%, 78.6% respectively, both deviations were small by comparing with the predicted value. CONCLUSION: This extraction process is reasonable and feasible by Plackett-Burman design and response surface analysis with good predictability. This study can provide experimental basis for further scale production of Sophora alopecuroides.

Study on the Separation and Purification Technology of Total Flavonoids from Sparganium stoloni by Box-Behnken Design- response Surface Methodology / 中国药房

OBJECTIVE： To optimize the purification technology of total flavonoids from Sparganium stoloniferum. METHODS： Separation and purification by macroporus adsorption resin， using sample solution pH， flow rate and concentration of eluent， the purification rate of total flavonoids as evalution indexes， the purification technology of total flavonoids from S. stoloniferum were optimized by Box-Behnken design-response surface methodology based on single factor test. Validation test was conducted. RESULTS： The optimal purification technology was sample solution pH 4.8， flow rate of eluent 2.0 BV/h， concentration of eluent 72％. The purification rate of total flavonoids in 3 batches of samples was 72.34％ （RSD＝1.77％， n＝3） in validation test， relative errors of which to predicted value （73.99％） was 2.13％. CONCLUSIONS： The optimal purification technology is stable and feasible， and can be used for the purification of total flavonoids from S. stoloniferum.

Study on Optimization of the Extraction Technology of Total Vitamin E in Euryale ferox by Box-Behnken Design-response Surface Methodology / 中国药房

OBJECTIVE： To optimize the extraction technology of total vitamin E in Euryale ferox. METHODS： With the extraction amount of total vitamin E as reference index， using extraction time， extraction times， ultrasound power and comminution degree as reference factors， single fator test and Box-Behnken design-response surface methodology was used to optimize the extraction technology of total vitamin E from E. ferox. The validation tests were conducted for 3 times （the amounts of E. ferox were 2.0， 20.0， 40.0 g）. RESULTS： The optimal extraction technology of vitamin E included that extraction time of 80 min， extraction times of 3 times， ultrasound power of 240 W， comminution degree of 80 mesh. In validation test， extraction rates of total vitamin E were 2.063， 2.103， 2.085 mg/g （RSD＝2.6％， 1.5％， 1.3％， n＝3）， the relative errors of which to predicted value （2.092 mg/g） were 0.14％， 0.53％ and 0.33％， respectively. CONCLUSIONS： The optimal extraction technology is reasonable， stable and feasible， and can be used for the extraction of total vitamin E in E. ferox.

Optimization of Extraction Technology of Flavonoids in Glycyrrhiza uralensis by Single Factor Experiment Combined with Box-Behnken Design-response Surface Methodology / 中国药房

OBJECTIVE： To optimize the extraction technology of the flavonoids from Glycyrrhiza uralensis. METHODS： Using total contents of four flavonoids， liquiritinapioside， glycyrrhizin， isoliquiritin apioside and formononetin as indexes， types and volume fractions of extraction solvents （water， ethanol）， volume of addition and extraction time as factors， based on single factor experiment， Box-Behnken design-response surface method was used to optimize the extraction technology of flavonoids from G. uralensis. Validation test was also conducted. RESULTS： The optimal extraction technology was 50 mL 50％ ethanol as extraction solvent， 0.200 g G. uralensis， ultrasonic extraction for 50 min. In validation test， the extraction amounts of liquiritinapioside， glycyrrhizin， isoliquiritin apioside and formononetin were 10.733 0， 27.784 9， 3.441 9， 0.429 1 mg/g， respectively （all RSDs＜3.0％， n＝3）. The average total extraction amount of four flavonoids was obtained was 42.388 9 mg/g， the relative error of which to predicted value （42.173 2 mg/g） was 0.52％ （n＝3）. CONCLUSIONS： The optimized extraction technology is simple， rapid and stable， and can be used for the extraction of flavonoids from G. uralensis.

Optimization of Phencynonate Hydrochloride Transdermal Patch Formulation by Box-Behnken Design-response Surface Methodology / 中国药房

OBJECTIVE:To optimize the formulation of Phencynonate hydrochloride transdermal patch. METHODS:Phencynonate hydrochloride transdermal patch was prepared by solvent evaporation method. Using 48 h accumulative transdermal volume as index,single factor test and Box-Behnken design-response surface methodology were used to optimize drug dosage,the amount of transdermal enhancers azone and pressure-sensitive adhesive,and evaluate the appearance,adhesion of the formulation prepared by the best prescription. RESULTS:The optimized formulation was as follows as 263 mg drug dosage,165 mg azone, 1.94 g pressure-sensitive adhesive and 1.6 g methanol. 48 h accumulative transdermal volume of prepared patch was(119.48 ± 2.95)μ g/cm2(n=5),related error of which to predicted value was 2.48%. The prepared patch showed smooth surface and incision,good adhesiveness. CONCLUSIONS:Phencynonate hydrochloride transdermal patch is prepared successfully,its accumulative transdermal volume is in agreement with predicted standard.

Study on rolling drying granulation of Rebiqing granules / 国际中医中药杂志

Objective@#Rebiqing granules were prepared and the rolling drying granulation process parameters were optimized.@*Methods@#According to the previous knowledge and experience, the feed rate, pressure and speed of rolling were used as the factors for investigation, and the primary forming rate and the solubility of the Rebiqing granule were taken as the evaluation indexes, and the Box-Behnken response surface method was used to optimize the rolling drying granulation parameters.@*Results@#The optimum rolling drying granulation parameters were as follows: feed rate was 8.5 Hz, rolling pressure was 6.0 Mpa and rolling speed was 8.5 Hz. After continuous production of 3 batches of validation, the Rebiqing granules had high molding rate and good solubility.@*Conclusions@#The rolling drying granulation processes were optimized by the experimental design, which could improve the robustness of the processes and control the stability of the product quality.

Optimization of Meloxicam Nanosuspensions Fast Dissolving Sublingual Films (MLX-NS-Fdsfs) by Box-Behnken Response Surface Methodology / 中国药学杂志

OBJECTIVE: To prepare and optimize meloxicam nanosuspensions fast dissolving sublingual films (MLX-NS-FDSFs) and to evaluate its in vitro dissolution characteristics. METHODS: Meloxicam nanosuspensions (MLX-NS) were prepared by pH-dependent dissolving-precipitating/high speed shearing method and then transformed into fast dissolving sublingual films (FDSFs). The formulations of MLX-NS-FDSFs were optimized by employing Box-Behnken design-response surface methodology with the amount of HPMC-E30, PEG-400 and MLX-NS as investigation factors, and particle size of reconstituted nanoparticles from MLX-NS-FDSFs, disintegration time and stretch length as indexes. The morphology, content uniformity and in vitro dissolution of the optimal formulation were also evaluated. RESULTS: The MLX-NS-FDSFs prepared by optimized formulation (35 mg·mL-1 HPMC-E30, 40 mg·mL-1 PEG-400, 10 mL MLX-NS) could fast disintegrate in (26.08±1.76) s, the tensile length was (1.51±0.13) mm, and the particle size of reconstituted nanoparticles from MLX-NS-FDSFs was (186.4±6.3) nm. There was a little deviation between the theoretically predicted value and the measured value. It showed that this model had a good prediction. Morphological analysis showed that well-dispersed MLX nanoparticles embedded in MLX-NS-FDSFs. The conformity of drug content was up to standard. MLX could be released in vitro as much as (91.75±8.05)% within five minutes. CONCLUSION: Using Box-Behnken design and response surface method to optimize MLX-NS-FDSFs is effective and feasible. MLX-NS-FDSFs can significantly increase the cumulative dissolution of MLX.

Optimization on Transformation from Chlorogenic Acid to Neochlorogenic Acid by Box-Behnken Design-response Surface Methodology / 世界科学技术-中医药现代化

Box-Behnken design-response surface methodology was used to optimize the transformation from chlorogenic acid to neochlorogenic acid.Based on single factor experiments,the experiment design were developed by box-benhnhen central composite design with causal factors of the reaction temperature,time and PH to neochlorogenic acid.The optimum transformation conditions were as follow:reaction temperature at 107℃,reaction time of 60 min,the PH of 4.72.Under the optimum extraction technology conditions,the productivity of neochlorogenic acid was 64.20％.Neochlorogenic acid was isolated and purified.The determination and characterization of neochlorogenic acid was detected by HPLC,1H-NMR,13C-NMR and ESI-MS.The results showed that the content of neochlorogenic acid reached to 98.78％ and the yield of 87.37％.

Extraction optimization for Yinsangju solid beverage by orthogonal design and Box-Behnken design-response surface methodology / 国际药学研究杂志

Objective To optimize extraction process of Yinsangju solid beverage(YSJ). Methods The extraction of YSJ was preliminarie optimized through the orthogonal design,and then further optimized by Box-Behnken design-response surface with the overall desirability(OD)of chlorogenic acid and polysaccharide content and yield of extract as evaluation indexes. Results The op?timum extraction of orthogonal design was as follow:10 times the amount of water,soaked 0.5 h,extracted 2 times,each time 1.5 h. The optimum extraction of Box-Behnken design was 10.82 times the amount of water,soaked 0.51 h,extracted 2 times,each time 1.77 h. Conclusion The test results show that the Box-Behnken response surface method optimization of extraction process parameters is more precise and more detailed and predictability is good,and the product quality is improved.

Extraction optimization for Yinsangju solid beverage by orthogonal design and Box-Behnken design-response surface methodology / 国际药学研究杂志

Objective: To optimize extraction process of Yinsangju solid beverage(YSJ). Methods: The extraction of YSJ was preliminarie optimized through the orthogonal design,and then further optimized by Box-Behnken design-response surface with the overall desirability (OD) of chlorogenic acid and polysaccharide content and yield of extract as evaluation indexes. Results: The optimum extraction of orthogonal design was as follow: 10 times the amount of water,soaked 0.5 h,extracted 2 times,each time 1.5 h. The optimum extraction of Box-Behnken design was 10.82 times the amount of water,soaked 0.51 h,extracted 2 times,each time 1.77 h. Conclusion: The test results show that the Box-Behnken response surface method optimization of extraction process parameters is more precise and more detailed and predictability is good, and the product quality is improved.

Optimization on Extraction Technology of Polysaccharide from Rhizoma Coptidis by Box-Behnken Design-Response Surface Methodology / 世界科学技术-中医药现代化

This study was aimed to optimize the extraction conditions of polysaccharides from Rhizoma Coptidis.With the R.Coptidis of extraction yield,polysaccharide yield and uronic acid yield as evaluation indexes,the impact of extraction temperature,extraction times,extraction duration and liquid-to-solid ratio on the process of R.Coptidis polysaccharides reflux extraction were investigated by the Box-Behnken design-response surface methodology.The results showed that the optimal extraction conditions were achieved and listed as follows:extraction temperature at 100℃,extracted 3 times with 3.8 h per each time,liquid-to-solid ratio of 1:15.7.It was concluded that the Box-Behnken design-response surface methodology was accurate,rational and feasible to optimize the extraction method of polysaccharides fromR.Coptidis.