Optimization of extraction process of prescription medicinal materials of compound Yangshe granules / 药学实践杂志

Objective Optimizing the extraction process of prescription medicinal materials of hospital preparation of compound Yangshe granules. Methods A high performance liquid chromatograph (HPLC) quantitative method was established for deacetyl asperulosidicacid methyl ester (DME) and ferulic acid (FC) of the active ingredient. Based on the content of DME, FC and the yield of extract, the extraction process of compound Yangshe granule extract was optimized using central composite design-response surface methodology. Results The established HPLC method of quantification of active components in compound Yangshe granules met the requirements of method validation. The optimal extraction process optimized by central composite design-response surface methodology were as follows: the weight of extraction solvent was 12 times of the medicinal slices, the alcohol concentration was 73% and the extraction time was 60 min. Conclusion In this study, the quantitative method of active components in compound Yangshe granule by HPLC has been successfully established, and the optimized extraction process is simple and easy to operate with good repeatability.

Optimization of the extraction process of Shangke Huoxue Granule by central composite design-response surface methodology / 国际中医中药杂志

Objective:To optimize the extraction process of Shangke Huoxue Granule.Methods:Taking the factors of extraction solvent multiple, extraction time and extraction times as investigation factors, and extraction amount of ferulic acid, paeoniflorin and the ratio of extraction as comprehensive evaluation indices, one-factor experimental design and central composite design-response surface methodology were adopted to optimize the extraction process of Shangke Huoxue Granule.Results:The binomial fitting equation was Y=96.16+2.42 A+0.63 B-3.76 AB-1.57 A2-1.87 B2 ( P<0.01). The optimal extraction process parameters were confirmed to be adding 16 times of water, 64 minutes each time, twice. The deviation rates between the measured values of three verification experiments and the predicted value were 2.00%, 3.23% and 0.66%. Conclusion:The established model of central composite design-response surface methodology has high predictability and the optimized extraction process is stable and feasible.

Trametes versicolor (L.) Lloyd as a source of thermostable serine protease: production and characterization

Proteases are ubiquitously present and are among the largest groups of commercially important enzymes. Here, we investigated a wood-rot basidiomycete Trametes versicolor (L.) Lloyd [Syn. Coriolus versicolor (L.) Quél.; Polyporus versicolor (L.) Fr.] as a source of the enzyme serine protease, its production, and optimized to obtain a higher yield of the enzyme.. The significant variables with optimized values for maximum production of the enzyme were temperature (30?C), incubation time (120 h) and wheat bran (10 g). The yield increased by 30.76% by statistically optimizing the media. The optimized temperature and pH for the maximum protease activity was 50?C and pH 7.0, respectively. The enzyme was purified through ion exchange (using DEAE cellulose 52 resin) and gel filtration chromatography (using Superdex 200 column). The purified enzyme had a retention time of 7 min in RP-HPLC. The enzyme was stable at a broad range of temperature (30-60?C) and pH (5.0-8.0) with a half-life of 58.72 min, Vmax of 37.17 ?M min/mL and Km of 0.657 mg/mL. Its activity was enhanced by Na+, Ca2+, Mg2+ ions and SDS surfactant. These properties make this enzyme a valuable candidate for industrial applications

High protein, gluten-free cookies made with rice, beans and avocado

Cookies are versatile foods that can supply specific needs and can be used as food vehicles to increase the intake of various nutrients. The objective was to create a gluten-free butter cookie based on rice flour (Oryza sativa). A central composite design 22 was used for analyzing the substitution of rice flour for bean flour (Phaseolus vulgaris, L.) (0-60%) and the substitution of butter for avocado puree (Persea americana) (0-100%). Response Surface Methodology were used to analyze the data with a significance of 10% (p<0.1) and a minimum R2 of 0.6. Variables analyzed were protein content (%), fat content (%), spread ratio, weight loss (%), water activity, moisture content (%), and ash content (%). Increases in the percentage of substitution of bean flour and avocado puree increased the amount of protein, ash, and moisture significantly. Fat content increased significantly following the decrease in avocado substitution. The minimum weight loss was obtained on intermediate values of bean flour. Water activity and spread ratio were not affected by changes in the variables measured. Three different formulas were obtained for the optimization: 46% bean flour and 86% of avocado puree, a formulation with an appropriate moisture range by reducing the lipid oxidation (59% bean flour and 82% avocado puree), and a formulation with 100% avocado (40% bean flour and 100% avocado puree). Sensory evaluation results of optimized treatments indicated that the formula with 46% bean flour and 86% avocado puree presented the highest global acceptance. Results from this study showcase the possibility of producing gluten-free cookies with good protein content.

Las galletas son alimentos versátiles que pueden suplir necesidades específicas y ser utilizados como vehículos para aumentar la ingesta de distintos nutrientes. El objetivo fue elaborar galletas de mantequilla libres de gluten a base de harina de arroz. Se realizó un diseño central compuesto 22 donde se estudió la sustitución parcial de harina de arroz por harina de frijol (Phaseolus vulgaris, L.) (0-60%) y la sustitución de la mantequilla por puré de aguacate (Persea americana) (0-100%). Los resultados fueron analizados por la Metodología de Superficie de Respuesta con un nivel de significancia del 10% (p<0.1) y con un mínimo R2 de 0.6. Las variables de respuesta fueron: proteína (%), grasa (%), diámetro/altura, pérdida de peso (%), humedad (%) y cenizas (%). A valores altos de las dos variables estudiadas la cantidad de proteína, de cenizas y de humedad aumentó significativamente. La cantidad de grasa se incrementó al utilizar bajos niveles de puré de aguacate. Los menores valores de pérdida de peso se obtuvieron en niveles intermedios de harina de frijol. La relación diámetro/altura no fue afectada por las variables estudiadas. Al optimizar se obtuvieron 3 formulaciones diferentes: 46% de harina de frijol y 86% puré de aguacate; 59% de frijol y 82% de puré de aguacate y otra (no estadística) 40% de frijol y 100% de puré de aguacate. Los resultados del análisis sensorial de las muestras optimizadas indicaron que la formulación con mayor aceptación global fue la elaborada con 46% de harina de frijol y 86% de puré de aguacate, concluyendo que es posible elaborar una galleta libre de gluten y con una adecuada cantidad de proteína.

Preparation and in vitro evaluation of berberine hydrochloride nanoemulsion oral drug delivery systems / 药学实践杂志

Objective To prepare berberine hydrochloride nanoemulsion, optimize its formulation composition and preparation process, and investigate its in vitro characteristics. Methods BBR-NE was prepared by water drop addition and pseudo-ternary phase diagram was drawn. The formulation of NE was optimized by central composite design-response surface methodology to choose the optimal formulation composition. The particle size, potential and appearance of the prepared BBR-NE were characterized. Results The optimal prescription of BBR-NE was determined as the oil phase Capryol 90 accounted for 32.84% of the system, the surfactant Tween-80 accounted for 33.90%, the co-surfactant 1,2-propylene glycol accounted for 16.95%, and water relative system accounted for 15.25%. The prepared NE was clear and transparent in appearance, regular in shape and uniform in size, with an average particle diameter of (68.85±8) nm, polydiseperse index of (0.245±0.03) and drug loading of 0.83 mg/g. The in vitro drug release results of NE showed that the in vitro drug release behavior was passive diffusion, which had a certain slow releasing effect and met the first-order release equation. Conclusion The BBR-NE can provide a new dosage form for the clinical use of berberine.

Optimization of extraction technology of total saponins from Trillium tschonoskii Rhizome by response surface method / 国际中医中药杂志

Objective:To optimize the ethanol reflux extraction process of total saponins in total saponins of Trillium tschonoskii Rhizome. Methods:On the basis of single factor tests, making the total extraction rate of three main compounds [paris saponin Ⅵ, paris saponin Ⅶ and pennogenin-3- O-α-L-rhamnopyranosyl-(1→4)-[O-α-L-rhamnopyranosyl (1→2)]- O-β-D-glucopyranoside (PRRG)] as the indicator, the optimal extraction parameter was selected with the main influencing factors: the ethanol concentration, solid-liquid ratio, and extraction time by the central composite design-response surface method.Results:The optimal extraction parameter for the ethanol extract of total saponins of Trillium tschonoskii Rhizome was as follows: ethanol concentration 69%, extraction time 1.9 h, and solid liquid ratio 1∶9.7. The binomial fitting complex correlation coefficient r = 0.966 1, and the deviation between the extracted predicted value and the actual value is 4.68%. Conclusion:The central composite design-response surface method is simple and reliable for the optimization of extraction process of total saponins of Trillium tschonoskii Rhizome.

Optimization of stir-frying with saltwater technology of Citrus reticulate by entropy weight method combined with central composite design-response surface method / 中国药房

O BJECTIVE To optimize stir-frying with saltwater technology of Citrus reticulata . METHODS Taking the contents of limonin ，nomilin and obacunone ，color difference value and free radical scavenging rate of 1，1-diphenyl-2-trinitrophenyl hydrazine （DPPH） as the indexes ，the entropy weight method was used for comprehensive evaluation. The stir-frying with saltwater technology of C. reticulata was optimized by central composite design-response surface method by using water-salt ratio ，stewing time，frying temperature and frying time as factors. RESULTS The optimal stir-frying with saltwater technology of C. reticulata included water-salt ratio of 8 ∶ 1（mL/g），stewing time of 22 min，frying time of 9 min and frying temperature of 158 ℃. After three times of validation tests ，the average comprehensive score of the optimized technology was 92.35（RSD＝2.19％），and its relative error with the predicted value （93.25）was 1.10％. CONCLUSIONS The optimal stir-frying with saltwater technology is stable and feasible.

Content Determination of Pulegone in Schizonepeta tenuifolia and Its Compound Preparation by Hollow Fiber Liquid-phase Microextraction Coupled with HPLC / 中国药房

OBJECTIVE：To establish t he metho d for the content determination of pulegone in Schizonepetae tenuifolia decoction pieces and its compound preparation. METHODS ：Hollow fiber liquid-phase microextraction coupled with HPLC （HF-LPME-HPLC） was adopted. Based on single factor tests ，HF-LPME condition of S. tenuifolia decoction pieces and its compound preparation （taking Compound S. tenuifolia granule as an expample ） was optimized by central composite design-response surface methodology using pulegone enrichment multiple as index ，with the concentration of sample phase solution （NaCl），extraction time and stirring speed as factors. Validation test was conducted. HPLC method was adopted to determine the content of pulegone. The determination was performed on Hypersil C 18 column with mobile phase consisted of methanol- 0.3％ phosphoric acid （gradient elution ）at the flow rate of 1.0 mL/min. The detection wavelength was set at 252 nm，the column temperature was 25 ℃. The sample size was 20 μL. The feasibility of HF-LPME-HPLC method established in this study was validated by using HPLC method stated in the item of S. tenuifolia decoction pieces in 2020 edition of Chinese Pharmacopoeia （part Ⅰ）as reference. RESULTS ：The optimum HF-LPME conditions included n-nonanol as the extraction solvent ，sample phase solution with 11％ NaCl and pH value of 7，stirring speed of 800 r/min，extraction time of 36 min. Results of HPLC methodology investigation showed that linear range of pulegone were 0.05-5 μg/mL（r＝0.999 0）. The limits of detection and quantitation were 0.4 and 1.3 ng/mL，respectively. RSDs of intra-day and inter-day precision were 1.8％-4.0％ and 1.5％-4.1％（n＝3），respectively. RSDs of reproducibility and stability tests （24 h）were all lower than 8％（n＝6）. Average recoveries of S. tenuifolia decoction pieces and Compound S. tenuifolia granule were 102.6％-105.1％ and 97.2％-102.3％，respectively；RSDs were not higher than 4.1％ and 6.2％（n＝3）. The average contents of pulegone in S. tenuifolia decoction pieces determined by pharmacopoeia method and established method were 0.84 mg/g（RSD＝4.3％ ，n＝3）and 0.87 mg/g（RSD＝5.5％ ，n＝3），respectively，with no significant difference （P＞0.05）. CONCLUSIONS ：The established HF-LPME-HPLC method can enrich and concentrate pulegone ， shows strong purification ability and high sensitivity ，and can be used to determine the contents of pulegone in S. tenuifolia decoction pieces and its compound preparation.

Progress on application of central composite design-response surface methodology in optimization of preparations in China / 药学学报

Central composite design (CCD) is one of the most commonly used design methods in response surface optimization and has been widely applied in the field of pharmaceutics to optimize preparations. On the 20th anniversary of the introduction of CCD into China, the paper reviews its application in domestic pharmaceutical researches. Based on the brief introduction of basic principle and operation steps of CCD, the mistakes emerging in the application of CCD are summarized, including conceptual confusion with Box-Behnken design and face-centered CCD as well as wrong designs. Besides, the issues concerning the selection of factors and responses are discussed. The article is helpful for researchers to comprehensively understand the CCD and facilitates the rational application of this method.

Study on the optimization of the preparation technic and pharmacological activity of Chuanxiong Rhizoma / 国际中医中药杂志

Objective:To optimize the preparation technic of Chuanxiong Rhizoma with vacuum steam method, and to investigate the anti-inflammatory and analgesic activity of Chuanxiong Rhizoma decoction pieces with Central Composite Design-Response Surface Method. Methods:Taking the content of ferulic acid as the evaluation index and the moistening temperature, moistening time and vacuum time as the observation indexes, the moistening technic of Chuanxiong Rhizoma was optimized by Response Surface Method, and selected the optimized plan. The anti-inflammatory and analgesic activities of Chuanxiong Rhizoma were investigated by auricle swelling induced by xylene and writhing induced by glacial acetic acid. Results:The optimum vacuum moistening technic was that the softening temperature was 80 ℃, the softening time was 50 min and the vacuum time was 45 min. The content of ferulic acid in Chuanxiong Rhizoma produced by this technic is highand could decreased the times of wrinkle reaction induced by acetic acid in mice, prolonged the latent period, and obviously or partially inhibitied the ear swelling degree induced byxylene in rats. Conclusions:The Response Surface Method technic of Chuanxiong Rhizoma is easy to operate with high accuracy. The vacuum steam treatment was more obvious than traditional technology group. It provides reference for the subsequent production of Chuanxiong Rhizoma decoction pieces and have the certain value for its promotion and application.

Optimization of the matrix formulation of Erhuang analgesic gels by central composite design-response surface methodology / 国际中医中药杂志

Objective:To optimize the matrix formulation of Erhuang analgesic gels. Methods:Central composite design-response surface methodology was adopted to optimize the best formulation of Erhuang analgesic gels by using carbomer 940, triethanolamine and glycerine as independent variables, the appearance, stability, viscosity and in vitro release of berberine hydrochloride as comprehensive evaluation indices. Results:The fitting regressing equation was Y= 82.25 + 4.95 A+ 5.19 B + 1.41 C+ 1.51 AB + 0.904 0 AC- 0.531 9 BC- 2.92 A2-1.80 B2-0.182 1 C2. P value of the model was less than 0.000 1, and the correlation coefficient r value was 0.977. The optimal formulation of Erhuang analgesic gels consisted of 1.84% carbomer 940, 1.30 times triethanolamine of carbomer 940 and 13.99 grams of glycerine. The average comprehensive scores of three verification experiments was 88.56, and the deviations from the predicted values were 2.93%, 2.85% and 1.55%. Conclusion:The formulation process by central composite design-response surface methodology was stable and the formulation of Erhuang analgesic gels has been optimized.

Integrated

The drug formulation design of self-emulsifying drug delivery systems (SEDDS) often requires numerous experiments, which are time- and money-consuming. This research aimed to rationally design the SEDDS formulation by the integrated computational and experimental approaches. 4495 SEDDS formulation datasets were collected to predict the pseudo-ternary phase diagram by the machine learning methods. Random forest (RF) showed the best prediction performance with 91.3% for accuracy, 92.0% for sensitivity and 90.7% for specificity in 5-fold cross-validation. The pseudo-ternary phase diagrams of meloxicam SEDDS were experimentally developed to validate the RF prediction model and achieved an excellent prediction accuracy (89.51%). The central composite design (CCD) was used to screen the best ratio of oil-surfactant-cosurfactant. Finally, molecular dynamic (MD) simulation was used to investigate the molecular interaction between excipients and drugs, which revealed the diffusion behavior in water and the role of cosurfactants. In conclusion, this research combined machine learning, central composite design, molecular modeling and experimental approaches for rational SEDDS formulation design. The integrated computer methodology can decrease traditional drug formulation design works and bring new ideas for future drug formulation design.

Application Of Central Composite Design For Citalopram Hydrogen Bromide Mouth Dissolving Films

Citalopram is an antidepressant used for treating major depressive disorder. In the current work Citalopram HBr is formulated as mouth dissolving film with enhanced drug dissolution. The Central Composite Design (CCD), employed to examine the effects of amount of HPMC E50 (A), amount of maltodextrin (B) and amount of glycerol (C) on response variables tensile strength, disintegration time and cumulative % drug release. 27 formulations prepared according to CCD and evaluated for physicochemical parameters and in vitro dissolution studies. Citalopram HBr mouth dissolving films formulated by employing solvent-casting method using HPMC E50, maltodextrin and glycerol, optimized for the effective dosage of superdisintegrants. The formulation CF21 with maximum tensile strength of 67.21±1.31 gm, least disintegration time of 9±1.60 sec and highest drug release of 98.41±1.81% is chosen optimal formulation with maximum content uniformity and folding endurance. It is evident from the above results that the developed formulation can be an innovative dosage form to improve the drug delivery, quick onset of action as well as improve patient compliance in the effective management of depression.

Fabrication of potential gastroretentive microspheres of itraconazole for stomach-specific delivery: Statistical optimization and in vitro evaluation

The premise of the study was to develop and optimize multiple unit gastroretentive microspheres of itraconazoleto prolong its localization in the stomach and analyzed using response surface methodology. The emulsion solventdiffusion evaporation method was used to prepare hollow microsphere of ethyl cellulose and Eudragit RS100 as lowdensity shell-forming polymers. The experimental design matrix was prepared using a central composite design tostudy the effect of various process parameters over response variables. The optimized microspheres showed a particlesize of 285.1µm, drug entrapment efficiency of 86.8%, buoyancy of 51.1%, and cumulative drug release of 77.80%.The experimental responses were in good harmony with the predicted values. The compatibility between drug andexcipients was determined by Fourier-transform infrared and differential scanning calorimetry analysis. The resultssignify that gastroretentive hollow microspheres are a promising vehicle to extend the retention time of itraconazolein the upper GI tract, and it can be floated in an acidic medium for a prolonged period.

Quality by design (Qbd) approach to develop stability indicating HPLC method for estimation of rutin in chitosan-sodium alginate nanoparticles

Rutin is a flavonoid glycoside, mainly consists of phenolic compounds, responsible for many biological activities. The objective of the present study was to develop and validate a precise, simple, robust, rapid and reliable reverse phase high -performance liquid chromatography (RP-HPLC) technique by using Qbd approach for evaluating the rutin in nanoparticles. Central composite design (CCD) was employed for optimizing the experimental conditions of RP-HPLC method. Buffer pH, methanol content in the mobile phase composition, flow rate, and wavelength were selected as independent variables whereas retention time, peak area, and asymmetry factor was selected as dependent variables. The retention time, peak area and asymmetric factor of rutin by using optimized independent variables were found to be 3.75 min, 1014.79 mV, and 1.26 respectively. The limit of detection and limit of quantitation values were found to be 0.005 µg/mL and 0.15 µg/mL respectively. For confirming linearity, accuracy, precision, and robustness, the optimized assay condition was validated as per ICH guidelines. The proposed method, which was optimized by QbD approach was found to be a suitable method for analyzing the rutin in chitosan-sodium alginate nanoparticles.

Optimization of the Formulation of Polygala japonica Cream by Central Composite Design-response Surface Methodology Based on AHP-CRITIC Analysis and Its Quality Evaluation / 中国药房

OBJECTIVE：To optimize the formul ation of Polygala japonica cream，and to evaluate the quality of prepared cream. METHODS ：With centrifugal stability ，heat resistance stability and viscosity as evaluation indexes ，the weight coefficient was determined by analytic hierarchy process （AHP），criteria importance through intercriteria correlation （CRITIC）method and mixed weighted AHP-CRITIC ，and the comprehensive score was calculated. The amount of octadecyl alcohol ，hexadecanol and mixed emulsifier （polysorbate 60 mixed with glycerin monostearate at the mass ratio of 2.82）in the formulation of P. japonica cream were screened by central composite design-response surface methodology. The optimized formulation was validated. P. japonica cream prepared by the optimal preparation was evaluated in terms of apperance ，particle，pH，stability and rheological characteristics. RESULTS ：The weight coefficients of centrifugal stability ，heat resistance stability and viscosity were 0.428 5， 0.415 6 and 0.155 9 respectively，according to the mixed weighted AHP-CRITIC. The optimal formulations were 1.96 g of hexadecyl alcohol ，5.17 g of octadecyl alcohol ，2.48 g of mixed emulsifier ，1.83 g of polysorbate 60，0.65 g of glyceride monostearate，1 g of benzyl alcohol ，5 g of propylene glycol ，6 g of isopropyl myristate and 5 g of P. japonica extract，and then added water to 100 g. Prepared cream was a light yellow fluid paste with particle size of 0.5-2.5 μm and pH value of 6.5；the results of centrifugal test ，heat resistance test and cold resistance stability test showed that the cream had no oil-water separation or thickened paste. The prepared cream was shear-thinning non-Newtonian fluid. CONCLUSIONS ：P. japonica cream is prepared successfully，which shows good apperance ，particle，acidity and stability.

Optimized Aqueous Extraction Conditions for Maximal Phenolics, Flavonoids and Antioxidant Capacity from Artocarpus heterophyllus (Jackfruit) Leaves by Response Surface Methodology (RSM)

@#Introduction: There are numerous studies on the therapeutic properties of Artocarpus heterophyllus. However, studies on the aqueous extraction of A. heterophyllus leaves are limited. This present study was conducted to optimize the extraction conditions of A. heterophyllus leaves to yield the highest phenolic, flavonoids and antioxidant contents. Methods: Response surface methodology (RSM) was employed to obtain a higher phenolic extraction parameter(s) of A. heterophyllus leaves using Central Composite Design (CCD). The antioxidant activity was then determined via ABTS (2,29-azinobis (3 ethylbenzothiazoline-6-sulfonic acid)) and DPPH (2,2-Diphenyl-1-picrylhydrazyl) assay and analysis of the individual phenolics was performed by high performance liquid chromatography (HPLC). Results: The optimum extraction conditions with higher phenolics content and antioxidant activity was achieved at 81°C, 100 min and 40 mL/g sample with a good desirability value of 0.87. Under these optimized parameters, total phenolics and flavonoids were 174.48 ± 4.05 mg GAE/g sample and 21.44 ± 0.05 mg RE/g sample, respectively. Meanwhile, antioxidant activity via ABTS and DPPH assays were 90.88% ± 0.09 and 87.22% ± 0.62, respectively. Finally, under optimal extraction conditions revealed 4 compounds identified as chlorogenic acid, quercetin, rutin and kaempferol. Conclusion: The optimisation are promising to improve phenolic yield and antioxidant activity in A. heterophyllus leaves. It also proved that A. heterophyllus leaves can be used as an alternative natural antioxidant especially in medicinal applications since all identified compound possess significant biological activities for human health.

Optimization of formulation process and in vitro evaluation of copper sulfide nanoparticles / 药学实践杂志

Objective To avoid the accumulation of copper sulfide (CuS) nanoparticles, prepare and optimize CuS nanoparticles, analyze the factors affecting the particle size and evaluate their photothermal properties. Methods Based on the single factor study, central composite design-response surface methodology was used to optimize the CuS nanoparticle formulation process. The morphology, particle size stability, photothermal conversion efficiency, photothermal stability of optimized CuS nanoparticles were characterized. The toxicity of CuS nanoparticles on 4T1 breast cancer cells and HK2 kidney cells was evaluated by CCK-8 method. In vitro photothermal experiment was used to investigate the ability of CuS nanoparticles on killing 4T1 breast cancer cells. Results The average hydration dynamic diameter of optimized CuS nanoparticles was (10.53±1.63)nm, the actual particle size of CuS nanoparticles showed by TEM image was (3.10±0.81)nm. It had good particle size stability, good photothermal conversion efficiency and photothermal stability. Within the concentration range of 100 μg/ml and 150 μg/ml，it showed no significant toxicity on 4T1 breast cancer cells and HK2 kidney cells, indicating the good stability of CuS nanoparticles. In vitro photothermal therapy showed that CuS nanoparticles had good ability to kill 4T1 breast cancer cells by photothermal. Conclusion The prepared CuS nanoparticles have a small particle size (less than 6nm) and a good photothermal effect, which is expected to solve the problem of CuS nanoparticles accumulation in vivo and make it better for tumor treatment.

Optimization of water-precipitation process in pretreatment process of Salviae Miltiorrhizae (Danshen) and Ligustrazine Hydrochloride Injection based on sequential central composite design / 中草药

Objective: To optimize the water-precipitation in the pretreatment manufacture process of Salviae Miltiorrhizae (Danshen) and Ligustrazine Hydrochloride Injection (SMLHI) based on the quality by design (QbD) concept and the sequential design. Methods: A design space was obtained by the global-type sequential design methodology combined with the fishbone-diagram risk analysis and central composite experiment based on global type sequential design method. The preliminary optimized zone of critical process parameters was extended in axial direction on the basis of the statistical result gained from the first central composite design. Then an updated multivariate linear regression model was fitted and a design space was delineated and verified. Results: According to the design space, the recommended operation space of the water-precipitation was as follows: when the pH value of the material was between 3.1 and 3.4, 3.25-5.00 times of water adding into the solution was recommened, the standing time was 7-17 h and the standing temperature was 7 ℃. Conclusion: This study introduces the sequential design into the process optimization of traditional Chinese medicine pharmaceuticals. Compared with the experimental design methods such as uniform space grid design and orthogonal design with a large number of samples, while samples cover the same feasible zone in a continuous operation form, sequential design methodology can effectively reduce the workload of the optimization experiment, avoid the waste of manpower and resources as well as guarantee the prediction ability of the fitting model.

Optimization of prescription process of curcumin-piperine polymeric micelles by central composite design-response surface method / 中草药

Objective: To optimize the prescription process of curcumin-piperine polymeric compound micelles (Cur/Pip F127/P123-PM) by central composite design-response surface method. Methods: The content of curcumin and piperine was determined by UPLC. The Cur/Pip F127/P123-PM was prepared by thin film hydration method. Based on the single factor test, the dosage, the mass ratio of F127 and the volume of water were used as independent variables, and the drug loading and entrapment efficiency of curcumin, entrapment efficiency of piperine and the micelle size were dependent variables, and next central composite design-response surface method of three factors and five levels was carried out. The analysis results showed and verified the optimal prescription. Finally, the optimal lyophilization conditions of the micelle preparation were initially screened. Results: The optimal preparation process was as follow: the dosage of curcumin and piperine was 12.96 mg and 0.69 mg, respectively; The mass ratio of F127 was 0.46, and the volume of water was 8.85 mL. The compound curcumin micelles prepared by the optimum formulation had the loading capacity of 5.63%, solubility of 1.27 mg/mL and entrapment rate of curcumin was 86.86%. The entrapment rate of piperine was 77.54%; The micelle size was 66.79 nm and the Zeta potential was close to zero. The lyophilized products prepared by using 8% mannitol as a protective agent had a good redispersion. Conclusion: The model established by central composite design-response surface method can be used to optimize the prescription of compound curcumin micelles, and the method had a high accuracy and good predictability advantage.