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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.
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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.
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Objective: To optimize the formulation of 1,8-cineole self-microemulsifying drug delivery system (1,8-Cin-SMEDDS), characterize it and investigate its cell uptake. Methods: By drawing pseudo-ternary phase diagram, the effective self-emulsifying region of 1,8-Cin-SMEDDS was determined, and the preliminary prescription was screened. Taking the particle size and drug loading as the index, the central composite design-response surface method was used to optimize and verify the prescription. Fluorescence microscope was used to observe the uptake of human umbilical vein endothelial cells (HUVEC) injured by high glucose. Results: The results showed that the best prescription of 1,8-Cin-SMEDDS was a mixture of soybean oil (7.5%) and 1,8-Cin (22.5%), HS15 (56%) as emulsifier, ethanol (14%) as co-emulsifier, and dripping pure water to 8 mL to obtain a translucent slightly bluish emulsion. The appearance of spherical droplets was observed by transmission electron microscope, and the average particle size and Zeta potential measured by laser particle size Zeta tester was (131.68 ± 1.44) nm and (-10.03 ± 1.63) mV, respectively; The entrapment efficiency estimated by HPLC was (99.890 ± 0.012)%, and the drug loading was (224.750 ± 0.028) mg/g. The results of HUVEC cell uptake assay showed that the uptake of 1,8-Cin-SMEDDS by cells was higher than that of free 1,8-Cin. Conclusion: The preparation method of 1,8-Cin-SMEDDS is simple and reproducible. The obtained method has good appearance, high entrapment efficiency, stable physical, and chemical properties, which can also promote cell uptake.
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Objective: Puerarin nanoemulsion (Pue-NE) was prepared with glycyrrhizic acid as a natural stabilizer, and its release characteristics in vitro were investigated. Methods: Data processing was performed using particle size and polydispersity index (PDI) as independent variables, and using the overall desirability (OD) as the evaluation index. The central composite design-response surface method was used to optimize the prescription, and the physical and chemical properties and release characteristics of Pue-NE prepared by the optimal prescription were investigated. Results: The best prescription for Pue-NE is puerarin at a concentration of 5.0 mg/mL, glycyrrhizic acid at a concentration of 1.75 mg/mL, and caprylic glyceride in an amount of 3.5 mL. The average particle size of the nanoemulsion is (184.5 ± 0.8) nm, the PDI is 0.088 ± 0.002, the zeta potential is (10.56 ± 0.35) mv, the conductivity is (98.3 ± 0.4) μs/cm, pH is 6.750 ± 0.005, solubility (4.970 ± 0.008) mg/mL, drug loading is (99.4 ± 0.2)%, turbidity (24.3 ± 1.0) cm-1 (n = 3). It was identified as O/W emulsion by dyeing method. TEM scanning results show that the droplets are spherical and uniform in size and the stability results showed that Pue-NE has good storage stability at 25 ℃. In vitro release results showed that Pue-NE has the greatest release in phosphate buffered pH 6.8 within 24 hours. Conclusion: The preparation of Pue-NE with glycyrrhizic acid as a natural stabilizer is not only simple and convenient, but also can effectively replace the use of traditional chemical synthetic stabilizers and improve the solubility of puerarin.
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Objective: To optimize the formulation of paeonol lipid microspheres (Pae-LM) through central composite design- response surface method and determine its in vitro release characteristics. Methods: Using the mean particle size and centrifugal stability constant (Ke) as evaluation indexes, the oil phase type and the ratio of composite oil, the amount of phospholipid and stearic acid, the type of emulsifier, the type and amount of stabilizer, the quality of PC and CH, the high-speed shear temperature and time, the homogenization pressure and time was screened in prescription process. Effects of dosage of paeonol and high pressure homogenizing pressure on the properties of Pae-LM preparation were investigated by central composite design-response surface method. The binomial model and multivariate linear regression model were used to establish the mathematical relationship between the indexes and the factors. According to the best mathematical model of evaluation index, the response surface was depicted and the best prescription was analyzed by the response surface method. According to the optimized formulation Pae-LM, the in vitro drug release characteristics were investigated. Results: The best prescription of Pae-LM was basically round, with mean particle size of (149.32 ± 0.57) nm, Zeta potential of (-36.01 ± 3.09) mV, encapsulation rate of (98.24 ± 0.32)% and drug-loading rate of (11.94 ± 0.04)%. There was a credible quantitative relationship between Ke and the two factors, and the binomialmodel was more reliable than the multivariate linear model. The cumulative release of paeonol drug substance at 12, 24 and 36 h were 71.84%, 85.21% and 95.07%, while the cumulative release of Pae-LM was only 57.21%, 59.66%, and 63.91% at 12, 24 and 36 h, respectively. The drug release was in accordance with the Ritger-peppas model. Conclusion: Central composite design-response surface method can be applied to optimize prescription of lipid emulsion microspheres. The optimized particle size of Pae-LM was suitable with a higher encapsulation rate, which can provide a reference for the development of paeonol cardiovascular delivery system.
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Objective: To optimize preparation of mitochondrial targeting hyperoside liposomes (DLD/Hyp-Lip), and study its stability in fetal bovine serum, in vitro release behavior and mitochondrial targeting. Methods: DLD/Hyp-lip was prepared by film dispersion method. Single factor experiment was carried out with entrapment efficiency and drug loading as indexes to investigate the effects of the ratio of phospholipids to hyperoside (Hyp) and DSPE-PEG (distearoyl phosphoethanolamine-polyethylene glycol) to DLD on DLD/Hyp-Lip. The formulation of DLD/Hyp-Lip was further optimized by central composite design response surface methodology. The appearance, size and potential of liposomes were observed by transmission electron microscope and particle size analyzer. The stability and drug release rate of liposomes in fetal bovine serum were evaluated by serum stability test and in vitro drug release test. The drug delivery system was evaluated by mitochondrial targeting. Results: The optimal formula of DLD/ Hyp-Lip was as follows: the ratio of total phospholipids to hyperoside was 12.50:1, the ratio of total phospholipids to cholesterol was 6.00:1, and the dosage ratio of DSPE-PEG to DLD was 3:5, the encapsulation efficiency was (95.57 ± 0.56) %, the drug loading was (8.55 ± 0.57) %. The prepared liposomes had good appearance, the particle size of the lip was (124.9 ± 3.4) nm, and the potential was (-6.2 ± 1.9) mV. It was stable in fetal bovine serum and accumulated in vitro release medium for 24 h. Mitochondrial targeting experiments showed that DLD/Hyp-Lip could promote the accumulation of drugs in the mitochondria. Conclusion: This method is simple and convenient, and can accurately and effectively optimize the preparation process of DLD/Hyp-Lip. The prepared DLD/Hyp-Lip has high encapsulation efficiency, small particle size, uniform distribution and good sustained-release effect, which lays the foundation for further in vivo research of DLD/Hyp-Lip. DLD/Hyp-Lip with hyperoside has good mitochondrial targeting of liver cancer cells and is a potentially efficient mitochondrial targeted drug delivery system for liver cancer cells.
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OBJECTIVE: To prepare simvastatin tablets and optimize its formulation by 3D printing technology. METHODS: A cylindrical tablet with a radius of 4 mm and a thickness of 4.8 mm were prepared by a 3D printer. The dosage of the adjuvant povidone 30(PVP K30), lactose/microcrystalline cellulose (MCC) and absolute ethanol were taken as an investigation factor, the cumulative dissolution rate of 5, 15 and 30 min were used as an evaluation index,and the central composite design-response surface method was used to optimize the formulation and verify, the effect of dissolution were researched by compared with the traditional preparation. RESULTS: The optimal formulation value: the ratio of PVP K30 was 30%, the mass ratio of lactose/MCC was 2.5, the ratio of absolute ethanol was 74%, and the cumulative dissolution in vitro of the printed tablets at 5, 15, 30 min was (45.7±0.5)%, (70.9±0.7)%, (89.7±2.3)% respectively, the deviation between the verification result and the predicted value were less than 5%. The preparation of dissolutioncurve is similar with commercially available formulations. CONCLUSION: The successful preparation of 3D printed simvastatin tablets is simple and the mathematical model is predictive.
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OBJECTIVE：To optimize the hot sand processing technology of Alpinia officinarum，and to provide scientific evidence for the standardized processing of A. officinarum. METHODS：The contents of galangin and curcumin in processed A. officinarum were determined by HPLC. Based on single factor test，using processing temperature and processing time as factors，comprehensive score of galangin and curcumin contents as index，central composite design-response surface method was used to optimize hot sand processing technology of A. officinarum，and the processing technology was validated. RESULTS：The optimal processing technology included processing temperature of 200 ℃ and processing time of 5.5 min. In validation tests，average comprehensive score was 94.38 （RSD＝1.02％），relative deviation of which to predicted value 93.74 was 0.68％. CONCLUSIONS：The optimized processing technology is simple and predictable. It can be used for hot sand processing technology of A. officinarum.
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Objective To optimize the preparation technology of thermo-reversible Yinhuang opthalimic gel by the central composite design-response surface method.Methods The poloxamer 407 and poloxamer 188 were used as the investigation factors, and the evaluation index was the gel temperature. Central composite design-response surface method was used to evaluate the mathematic relation between the evaluation index and tow investigation indexes to identify the optimum prescription.Results According to the quadratic models, it was found that there was reliable quantitative relation between the evaluation index and two investigation indexes,among which the optimun dosage was 20％ for P407, 1％ for P188, 0.1％ for hyaluronic acid, 0.01％ for benzalkonium chloride, 0.02％ for EDTA.Conclusions This method is reliable and feasible, whicn can realize the prescription optimization of the gel.
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OBJECTIVE: To prepare huperzine A micro-porous osmotic pump pellets and to investigate the pharmacokinetic properties in Beagle dogs. METHODS: The extrusion-spheronisation method was used to prepare the core of huperzine A pellets which then coated by fluid-bed coating technology. Central composite design-response surface method was used to optimize the prescription of coating layer.Then Zero-order, First-order and Higuchi equation of cumulative release with time were fitted to study its release characteristics.The commercially available huperzine A tablets were used as reference preparations to investigate the in vivo pharmacokinetics of huperzine A micro-porous osmotic pump pellets, and the bioequivalence of the two preparations were compared. RESULTS: The formula of coating was optimized as followsEC of 61.5%, PEG400 of 10.5%. Zero-order kinetics existed in the release of the pellets in 24 h. Moreover, the osmotic pressure-controlled delivery was greatly responsible for drug release. In vivo study showed that tmax and ρmax of huperzine A micro-porous osmotic pump pellets were significantly lower than that of the reference preparation, and its t1/2 was significantly prolonged compared with the reference preparation, the relative bioavailability was 95.8%. CONCLUSION: Huperzine A micro-porous osmotic pump pellets had a better sustained release effect in the Beagle dog and have a good correlation in vivo.
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Objective To optimize the extraction technology of Compound purgative Moringa Oleifera by central composite design-response surface method. Methods The content of isoquercetin and astragalin, the yield of dry extract and overall desirability (OD) were used as the evaluation indexes; the factors such as water addition, extraction times and time for extraction were employed to optimize extraction technology of central composite design-response surface method. Results Optimal extraction technology was as follows: 3 times extracted with 10-fold the amount of water for 1 h each time. Conclusions Central composite design-response surface method was suitable for optimizing extraction technology of compound purgative Moringa Oleifera.
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Objective To fabricate the asiaticoside loaded capsosomes with CaCO3 as core (CASI) and establish the method for determination of entrapment efficiency, then the prescription of formulation and preparation process were screened with the entrapment efficiency as index. Methods An HPLC method was established to determine the contents of asiaticoside. CASI were prepared by co-precipitation method and layer-by-layer assembly technique. The encapsulation efficiency was determined by a proved centrifugation. In this study, the effect of concentrations of capsule material, pH and rotating speed on encapsulation efficiency was investigated. Results The encapsulation efficiency obtained by centrifugation was accurate and reliable. The optimized prescription was concentrations of 1 mg/mL capsule material with pH value 12, pH 7.9 of liposomes, two precursor layers, one liposome layer, rotating speed 500 r/min, and 15 min of reaction time. The CLSM images confirmed the structural integrity of the CASI. Conclusion This formulation endowed with high encapsulation efficiency, and the CASI observed by CLSM turned out to be globular shapes and was narrow in size distribution.
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Objective To optimize the prescription and preparation technology of brucine nanostructured lipid carriers (B-NLC). Methods The method of "the solvent emulsification ultrasound" was used to prepare B-NLC. The prescription and preparation was optimized using a single factor method combined with central composite design-response surface methodology (CCD-RSM). Results The resultant B-NLC was transparent liquid with light blue opalescence. The optimal conditions were that the dosage of drugs was 1.28 mg, the mass concentration of poloxamer 188 was 1.08%, and the ratio of solid lipid to liquid lipid was 1.45:1. The obtained NLC showed the average particle size of (136.89 ± 4.23) nm with a polydispersity index of 0.289 ± 0.005 and a zeta potential of (-34.46 ± 0.31) mV. The entrapment efficiency was calculated to be (68.98 ± 2.06)%, and the drug loading content was (1.90 ± 0.06)%. Conclusion B-NLC prepared by solvent emulsification ultrasound had a high entrapment efficiency and a narrow particle size distribution. The method was easy and simple and can be used to optimize the prescription and preparation of B-NLC, which provides a foundation for the further in vivo research of brucine.
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Objective To optimize the best prescription of Yuanhu Zhitong Oral Disintegrating Tablets (YZODT). Methods Using the single factor test, the prescription of the tablets was optimized by central composite design-response surface methodology (CCD-RSM) with the tablet wetting time and the disintegration time limit as evaluation index, so as to determine the best preparation process. Results The dosages of the optimized prescription of MCC, L-HPC, and PVPP were 30%, 15%, and 5%, respectively. The average disintegration time of the optimized YZODT was 42.89 s, and the deviation from the predicted value was 3.27%. Conclusion The optimized YZODT has the advantages of fast disintegration, moderate hardness, convenient use, and simple process.
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AIM To prepare the thermosensitive intestinal gels of Houttuynia cordata Thunb volatile oils hydroxypropyl-β-cyclodextrin (HPCD) inclusion compound.METHODS For the gels prepared by cold dissolving method,poloxamer 407 consumption and poloxamer 188 consumption were taken as influencing factors,together with phase transition temperature as an evaluation index,central composite design-response surface method was applied to optimizing the formulation.With 2-undecanone as an index component,the gels' dissolution rate and in vitro release rate were investigated by non-membrane dissolution method and dialysis bag method respectively,whose stability was then evaluated by high temperature (40,60 ℃),low temperature (4 ℃),strong light [(4 500 ±500) 1x] and acceleration (three months) tests.RESULTS The optimal conditions were determined to be 20.61％ for P407 consumption and 3.03％ for P188 consumption,the phase transition temperature was 36.5 ℃.Within the time range of 30-150 min,the HPCD inclusion compound gels exhibited higher accumulative dissolution rate than the volatile oils gels,which tended to be consistent in 150-210 min,but the former exhibited higher accmulative release rate (0-50 h) than the latter all the time.The obtained gels showed good stability at low temperature,whose appearance,characteristic (except for high temperature) and pH were stable at high temperature,strong light and acceleration with obviously decreased 2-undecanone content.CONCLUSION The thermosensitive intestinal gels of Houttuynia cordata Thunb volatile oils HPCD inclusion compound should be stored at low temperature (4 ℃).
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Objective To optimize extraction technology of Compound Danggui Buxue Decoction. Methods On the basis of single factor test, factorial design, and fastest rise test, yield and weight sum of extraction efficiency of ferulic acid, paeoniflorin and ligustilide were set as response, and central composite design-response surface method was used to optimize the extraction technology of Danggui Buxue Decoction. Results The optimum conditions consisted of ultrasonic-wave extraction for 60 min, ethyl alcohol concentration 36％ and the ratio of material to solvent = 1:94. Conclusion This method has high extraction efficiency, easy operation and good predictability.
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@#To prepare a budesonide rectal thermogel. The gel solution was prepared by cold method, and the gelation temperature of the gel solution was determined by reverse tube method. The amount of poloxamer 407(P407), poloxamer 188(P188)and hydroxy propyl methyl cellulose(HPMC)was optimized by central composite design/response surface method. The in vivo gelation character was investigated after rectal administration of the budesonide thermogel into the rat, and the in vitro drug release from the gel was examined by the Franz diffusion cell method. Finally, the optimal formulation includes 0. 002% budesonide, 0. 93% HPMC, 2. 00% P188, and 18. 31% P407. It is preferable to obtain the appropriate formulation for budesonide rectal in situ thermogel, which can achieve wide distribution and adhesion to the rectum, as well as long-term drug release.
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AIM To prepare nanosuspensions of flavonoids from Glycyrrhizae Radix et Rhizoma and to determine the in vitro dissolution rate.METHODS Precipitation-high pressure homogenization method was adopted in the preparation of nanosuspensions.With mean particle size and polydispersity index (PDI) as evaluation indices,concentrations of flavonoids,povidone K30 (PVP K30) and polyethylene glycol 400 (PEG 400) as influencing factors,central composite design-response surface method was applied to optimizing the preparation.For the freedried powder prepared by freeze-drying method,the optimal kind and ratio of lyoprotectant were screened.Then the in vitro dissolution rates of freeze-dried powder and physical mixture were compared.RESULTS The optimal conditions were determined to be 10.00 mg/mL for flavonoids' concentration,and 2.30 mg/mL for both PVP K30 and PEG 400 concentrations,the mean particle size and PDI were (172.3 ± 1.2) nm and 0.175 ± 0.004,respectively.The optimal lyoprotectant was 5％ mannitol-lactose (3 ∶ 2),the mean particle size and PDI after redissolution were (239.7 ±2.1) nm and 0.193 ±0.032,respectively.The in vitro dissolution rate of lyoprotectant reached 87.7％ within 60 min,which was much higher than that of physical mixture (less than 30％).CONCLUSION Nanosuspension can effectively improve the in vitro dissolution rate of flavonoids from Glycyrrhizae Radix et Rhizoma.
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AIM To prepare thermo-sensitive diammonium glycyrrhizinate binary liposome gel and to evaluate the in vitro drug-release behaviors.METHODS Cold dissolution method was adopted in the preparation of gel.With gel transition temperature as an evaluation index,amounts of Poloxamer 407 (P407),Poloxamer 188 (P188) and polysaccharides from Bletillae Rhizoma as influencing factors,central composite design-response surface method was applied to optimizing the formulation.Then the in vitro drug-release behaviors were evaluated by HPLC and Franz vertical diffusion cell method.RESULTS The optimal formulation was determined to be 18％ for P407 amount,4％ for P188 amount,and 0.6％ for polysaccharides' amount,the gel transition temperature was (37.5 ± 0.3) ℃.The accumulative release rate of obtained thermo-sensitive binary liposome gel was (65.52 ± 0.63) ％ within 48 h,which showed more obvious sustained-release effect as compared with liposome and thermosensitive gel.CONCLUSION Thermo-sensitive diammonium glycyrrhizinate binary liposome gel can reduce drug-release rate and increase its retention time in the rectum.
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OBJECTIVE:To optimize the extraction technology for organic acids in Crataegi fructus. METHODS:Based on sin-gle factor test,using liquid-solid ratio,extraction time and ethanol volume fraction as independent variables,extraction yield of or-ganic acids as dependent variable,central composite design-response surface method was used to optimize the extraction technology of organic acids in Crataegi fructus. RESULTS:The optimal extraction technology was as follow as liquid-solid ratio of 18.5:1, adding 75% ethanol,reflux extraction twice,2.0 h each time. Average extraction yield of organic acids in verification test was 5.22%(RSD=2.70%,n=3),with 1.75% relative error of the predicted value(5.13%). CONCLUSIONS:Optimized extraction technology for organic acids in Crataegi fructus is simple,with good reproducibility and predictability.