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OBJECTIVE：To preliminarily optimize the preparation technology of Ligustrazine pellicle ，and to study its in vitro percutaneous permeation characteristics. METHODS ：With the amounts of PVA- 124，ethyl alcohol ，glycerin，tween-80 and azone as factors ，single factor experiment was used to optimize the Ligustrazine pellicle matrix formulation ；modified scoring standard was used to evaluate the film formation time ，film formation ability ，ductility，uniformity and the presence of bubble. On the basis of the optimal matrix formulation ，the pellicle with different loading amount of ligustrazine （300，250，200，150，100，50 mg/mL） was prepared and its maximum loading amount was investigated. HPLC method was adopted to determine the content of ligustrazine，and methodology investigation was conducted. Isolated back skin of rats were collected ，the percutaneous permeation test was conducted for high ，medium and low loading amount （100，75，50 mg/mL）of Ligustrazine pellicle. At 15，30，45，60， 75，90，120，150，180 min，the sample was taken and the permeation rate of ligustrazine was calculated. RESULTS ：When the amounts of PVA- 124，ethyl alcohol，glycerin，tween-80 and azone were 2.5 g，7.0 mL，1.97 mL，0.07 mL，0.28 mL（in terms of 50 mL formulation amount ），the optimal matrix formulation of Ligustrazine pellicle was obtained. The maximum drug loading amount of ligustrazine was 100 mg/mL. The linear ranges of ligustrazine was 3.125-100 μg/mL. The specificity，precision， reproducibility，recovery and stability investigation of content determination method of ligustrazine were all in line with the requirements（RSD＜2％）. The permeation rate of high ，medium and low loading amount of Ligustrazine pellicle were 608.42， 384.19，158.20 μg（/ cm2·h）. CONCLUSIONS ：According to the optimized formulation ，the prepared Ligustrazine pellicle had a short film forming time ，stable and re liable quality ； the drug-loading amount was up to 100 mg/mL. The pellicle with drug-loading amount of 75 mg/mL had reached the penetration rate range of effective plasma concentration of ligustrazine treatment.
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OBJECTIVE: To optimize the formulation of alginate mPEG-b-PLGA nanoparticles by Box-Behnken response surface method. METHODS: Using synthetic 10% mPEG-b-PLGA as nanoparticles matrix materials, the insulin-loaded alginate mPEG-b-PLGA nanoparticles were prepared by modified double emulsion-solvent evaporation method.To optimize the formulation,the mass ratio of insulin to polymer,the volume ratio of oil phase to external water and the concentration of poloxamer 188(F68) were selected as independent variables, with encapsulation efficiency(EE%), loading capacity(LC%) as the dependent variables.The formula was optimized by Box-Behnken design and response surface methodology.The particles size, polydispersity index(PDI), Zeta potential and morphology of optimized nanoparticles were measured by dynamic light scattering(DLS), electrophoretic light scattering(ELS) and transmission electron microscope(TEM), respectively.The in vitro release profile of nanoparticles was investigated. RESULTS: The optimal formulation was as follows:the mass ratio of insulin to mPEG-b-PLGA was 14.67:100, the oil phase to external water ratio was 1:3.32 and F68(W/V) concentration was 2.01%, respectively. The entrapment efficiency, the loading capacity, average particles size and Zeta potentials were(83.61±0.38)%,(10.90±0.23)%,(271.8±3.5) nm and(-54.27±2.75) mV, respectively, which correspond closely to the predicted values.The optimized insulin-loaded nanoparticles performed good sustained release property in pH 7.4 medium. CONCLUSION: The Box-Behnken design and response surface methodology is an effective and efficient method, which can be applied in the formula optimization of alginate mPEG-b-PLGA nanoparticles preparation.The optimized nanoparticles can be served as a promising insulin or proteins drug nanocarriers for its good sustained release property.
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OBJECTIVE： To establish content determination method of Triptolide-glycyrrhetic acid compound microemulsion， optimize the formula and investigate its physicochemical properties and release rate in vitro. METHODS： The content of Triptolide- glycyrrhetic acid compound microemulsion was determined by UPLC. The determination was performed on ACQUITY UPLC BEH C18 column with mobile phase consisted of 0.1％ formic acid aqueous solution-acetonitrile （gradient elution） at the flow rate of 0.4 mL/min. The column temperature was 40 ℃. The detection wavelength was set at 218 nm， and sample size was 5 μL. Pseudo-ternary phase diagrams were drawn by water titration method. Using oil phase， surfactants and co-surfactants as index， the formula was optimized， and in intro release characteristics was investigated by in vitro release test. RESULTS： The linear range of triptolide and glycyrrhetinic acid were 1-40 μg/mL（r＝0.999 7） and 10-400 μg/mL（r＝0.999 8）， respectively. The limits of quantitation were 0.5 and 0.8 μg/mL； the limits of detection were 0.1 and 0.2 μg/mL. RSDs of precision， stability and reproducibility tests were all less than 2％. Average recoveries were 100.32％-101.15％ （RSD＝0.36％， n＝6）， 99.78％-101.42％ （RSD＝0.59％，n＝6）. The optimal formula included that medium chain triglyceride as oil phase， polyethylene glycol hydroxy stearate as surfactants， ethanol as co-surfactants， water as water phase， the proportion of them was 8 ∶ 28 ∶ 14 ∶ 50. The obtained microemulsion was O/W type， being transparent and clear， with average diameter， average polydispersity index and average viscosity of （62.38±3.44） nm， 0.096±0.001 and （26.84±1.10） mPa·S. Within 24 h， cumulative release rates of triptolide and glycyrrhetinic acid in obtained microemulsion were 99.8％ and 99.7％ （in PBS pH 2.0）， 99.3％ and 99.4％ （in PBS pH 7.4）， 98.9％ and 98.4％ （in PBS pH 9.0）， respectively. Triptolide and glycyrrhetinic acid released faster in the single microemulsion than in the compound microemulsion. CONCLUSIONS： Established content determination method is simple and stable. The optimized formula is stable and feasible. Obtained iriptolide-glycyrrhetinic acid compound microemulsion show better sustained-release effect than sigle microemulsion.
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OBJECTIVE： To prepare Capsaicin solid dispersion， to optimize its formulation and characterize the dispersion. METHODS： Capsaicin solid dispersion was prepared by melting method using P188 or PEG4000 as carrier. Using 60 min accumulative dissolution rate in vitro as index， orthogonal test was used to optimize type of carrier， drug ratio and stirring time. Validation test was conducted. The stability of Capsaicin solid dispersion within 0， 30， 180 d was investigated at 40 ℃ under the relative humidity of 75％， and X-ray diffraction （XRD） was used to analyze whether there were peaks. Capsaicin solid dispersion was characterized by differential scanning calorimetry （DSC） and XRD. RESULTS： The optimized formula included P188-PEG4000 as carrier， capsaicin-P188-PEG 4000 mass ratio of 1 ∶ 5 ∶ 3， stirring for 20 min. Accumulative dissolution rate in vitro of Capsaicin solid dispersion was 84.6％ within 60 min （n＝3）， and the preparation kept stable within 180 d [RSD of content was 3％ （n＝3）； XRD showed that there was no peak]. The phase characteristics showed that capsaicin was highly dispersed in the amorphous or molecular state in carrier. CONCLUSIONS： The optimized technology can be used to prepare Capsaicin solid dispersion， and improves more than 80％ dissolution rate in vitro at 60 min. It is stable， simple and feasible.
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Objective To optimize the formulation of rutaecarpine lipid liquid crystalline nanoparticles (Rut-LLCN) by Box-Behnken design-response surface methodology. Methods Rut-LLCN were prepared by precursor injection-high pressure homogenization method. A three factor and three-level Box-Behnken design was employed with the glyceryl monoolein quality, percentage of poloxamer in glyceryl monoolein and the rutaecarpine quality as independent variables, the entrapment efficiency, drug loading, mean particle size and polydispersity index as the dependent variables to sereen the optimal formaula. Results Optimized prescription was GMO 450 mg, F127-GMO 12%, and Rut 20 mg. All items of optimized prescription were similar to target values. According to the optimized prescription, the entrapment efficiency, drug loading, average particle size, and PDI of Rut-LLCN were (84.02 ± 7.99)%, (3.24 ± 0.30)%, (186.90 ± 13.50) nm, and 0.313 ± 0.020, respectively. Conclusion The prescription optimization model of Rut-LLCN was optimized by Box-Behnken designs-response surface methodology, and entrapment efficiency, drug loading, mean particle size, and PDI of Rut-LLCN are measured to investigate the model.
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OBJECTIVE:To optimize the formula of Captopril timing osmotic pump tablets. METHODS:Using accumulative release rate (Q) as index, single factor test was used to investigate the effects of blocking layer coating weight gain, semipermeable membrane coating weight gain,the type of polyepoxide (PEO),the amount of PEO (3 × 105) and HPMC in drug bearing layer,the amount of PEO (7 × 106) and NaCl in booster layer on drug release of Captopril timing osmotic pump tablets. Based on single factor investigation,using comprehensive score of release behavior(L)as index,the amount of PEO(3×105)and HPMC in drug bearing layer,the amount of PEO(7×106)and NaCl in booster layer as factors,L9(43)orthogonal test was used to optimize the formula of tablet core validation test was conducted. RESULTS:The optimal formula of tablet core included PEO(3× 105)71 mg and HPMC 15 mg in drug bearing layer,PEO(7×106)61 mg and NaCl 18 mg in booster layer,coating weight gain 7％ and semipermeable membrane coating weight gain 10％ in blocking layer. The osmotic pump tablet prepared by optimized formula released after 4 h;in vitro drug release regression equation was Q=5.118t-21.441(R2=0.9956),which was in line with zero-order release characteristics. CONCLUSIONS:The optimal formula is stable,feasible and controllable in quality,and can provide reference for further development of Captopril timing osmotic pump tablets.
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Objective: To optimize the formula and preparation process of metronidazole thermosensitive in situ gel.Methods: The temperature of gelation and 24-h cumulative release were used as the evaluation indices, and the orthogonal tests were carried out to investigate the amounts of poloxamer 407 (P407), poloxamer 188 (P188), sodium alginate and polyethylene glycol 4000 (PEG 4000) to screen the best formula of thermosensitive in situ gel.The in vitro release of metronidazole thermosensitive in situ gel was determined by HPLC and compared with that of commercially available gel.Results: The optimum formula of thermosensitive in situ gel was P407 of 20%, P188 of 18%, sodium alginate of 0.1% and PEG 4000 of 1.5%.The release rate of metronidazole thermosensitive in situ gel was high, and the temperature of gelation was suitable.Compared with that of the commercially available gel, the vaginal retention of the in situ gel was significantly improved.Conclusion: The formula of the in situ gel is reasonable and the preparation process is feasible.
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Objective:To optimize the formula of artesunate dry suspension, and evaluate the quality. Methods:With sedimenta-tion volume ratio, redispersibility and loss on drying as the indices, single factor and orthogonal test were adopted to study the variety and amount of fillers, suspending agents, binders and disintegrating agents to optimize the formula. HPLC was used to determine the content of artesunate in the preparation. Different media and speed were used to investigate the dissolution behavior of artesunate dry suspension. The stability of the preparation was studied under the conditions of temperature (30 ± 2) ℃ and relative humidity (75 ± 5) % for four months. Results:The optimal formula of artesunate dry suspension was as follows: sucrose as the filler, xanthan gum (8%) and CMC-Na (12%) as the suspending agent, MCC (15%) as the disintegrant and 6% PVP K30 (in 50% ethanol solution) as the adhesive. Totally 4 batches of samples were prepared with the optimal formula, and their label contents were all above 95%, the sedimentation volume ratios were all higher than 0. 9 and the dissolution was more than 80% in 20 min. All the indices of samples met the requirements without significant change in 4 months. Conclusion:The preparation process of artesunate dry suspension is simple, reproducible and stable.
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Objective:To optimize the base formula of boric acid cream,and investigate its quality. Methods:Using central composite design-response surface methodology,with the viscosity of cream as the index,the amounts of Cremophor A6,Cremophor A25,cetyl alcohol,stearyl alcohol,isooctadecyl isooctadecanoate,jojoba oil and light liquid paraffin were optimized. The appearance characteristics,particle size,viscosity and stability of the preparation and the content of boric acid were studied. Results:The optimal conditions were as follows:50 g Cremophor A6-Cremophor A25(3 ∶2),65 g cetyl alcohol-stearyl alcohol(3∶7),and 125 g isooctadecyl isooctadecanoate-jojoba oil- light liquid paraffin(5 ∶3 ∶2). According to the optimal formula,the cream showed the property of semi-fluid cream,the content of boric acid was 98. 5% of the labeling amount,and the viscosity was about 1. 64 × 104 mPa·s. The predicted value was equivalent to the measured one,and the stability of the preparation was promising. Conclusion:The central composite design-response surface methodology used in the base optimization of boric acid cream is simple with high precision and good predictability,and the quality of the preparation is stable and controllable.
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To screen the optimal formula and evaluate the quality of testosterone undecanoate ( TU) binary ethosomes to lay the foundation for the transdermal delivery system of TU. Methods:The mixture of ethanol and propylene glycol was used as the softeners, and TU binary ethosomes were prepared by ethanol injection method. The ratio of TU to lipids ( A) , the quality percentage of the mixture of ethanol and propylene glycol ( B) and the ratio of ethanol to propylene glycol ( C) as the influencing factors, and the entrapment efficiency as the index, an orthogonal test was used to optimize the formula of TU binary ethosomes. The morphology, size, zeta potential, in vitro drug release and stability of TU binary ethosomes were studied. Results:The optimal formula of TU binary etho-somes were as follows:the ratio of TU to lipids was 1∶15, the quality percentage of the mixture of ethanol and propylene glycol was 10% and the ratio of propylene glycol to ethanol was 6∶4. The optimal TU binary ethosomes were concentric circles under an optical microscope with uniform size, and the average size was (185. 5 ± 52. 8)nm, zeta potential was ( -15. 87 ± 0. 26)mV, and the entrap-ment efficiency was (79. 14 ± 0. 66)%. TU release from the binary ethosomes in vitro was fitted the first-order equation:Q=20. 79t-11. 01 (r2 =0. 998 4). Under the high temperature, the entrapment efficiency was decreased significantly, while under the other test conditions, all the indices of TU binary ethosomes showed no significant difference. Conclusion:The optimal TU binary ethosomes are easy to be prepared with promising quality and sustained release property in vitro, which are valuable to be studied further.
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Objective To optimize the formula of konjac glucomannan-paeonol matrix tablets. Methods The formula of paeonol matrix tablets was optimized by the orthogonal design with the accumulative release rate in vitro as index, with the viscosity of konjac glucomannan ( KGM) , the amount of KGM and lactose as influence factors. Results The optimized formula was as follows:the viscosity of konjac glucomannan was 20 000 mPa·s, KGM 30%, lactose 20% and the release in vitro fit into the Higuchi equation. Conclusion The formula of the paeonol matrix tablets is reasonable and the tablets have well release effect in vitro.
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Objective:To optimize the formula of metronidazole and borneol sustained-release films. Methods: The mass ratio of Rhizoma Bletillae polysaccharide and polyvinyl alcohol 124(PVA-124) and the dosage of glycerol and sodium carboxymethyl cellulose ( CMC-Na) as the influencing factors ,the appearance of films and the release rate of metronidazole at 0. 5h and 4h as the comprehen-sive evaluation indices, the formula of the film-forming materials was optimized by orthogonal test. Results:The mass ratio of Rhizoma Bletillae polysaccharide and PVA-124 was the key factor affecting the quality of the films. When the mass ratio of Rhizoma Bletillae pol-ysaccharide and PVA-124 was 20∶80, and the dosage of glycerol was 3. 5g and that of CMC-Na was 0. 14g, the appearance of the films was satisfied, the release rate of metronidazole at 0. 5h and 4h was 25. 17% and 69. 64%, respectively, and the average cumulative re-lease rate at 8h was over 90%. Conclusion:The films prepared by the optimized formula are flat, smooth, clean and moderately soft, which can not only remain the drug release characteristics of the films made by the original formula, but also exhibit the pharmacologi-cal effect of Rhizoma Bletillae.
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Objective: To optimize the formula of andrographolide-loaded PLGA microsphere. Methods: The microspheres were prepared by the solvent evaporation method using PLGA as drug carriers. The effects of the concentration of PLGA and PVA, and the oil-water phase ratio were investigated. According to the drug loading amount and encapsulation efficiency, the formula was optimized by Box-Behnken design and response surface method. Results: The optimal formula was as follows: PLGA concentration of 0.20 g/mL, PVA concentration of 18 mg/mL, and oil-water phase ratio of 1:90, respectively. The drug loading amount of the microsphere was (47.21 ± 2.36)% and the encapsulation efficiency was (90.15 ± 3.48)%, which were very close to the predicted values. Conclusion: It is effective and feasible to apply Box-Behnken design and response surface method for the formula optimization of the andrographolide-loaded PLGA microsphere.
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Aim: To study the effects of molecule weight,the N/P ratio,solvent and ionic strength on the formation and surface properties of PEI/DNA complexes,and study its transfection efficiency.Methods: The N/P ratio of the prepared PEI/DNA complexes was optimized using gel electrophoresis and UV quantitative assay.The particle size and surface charge of the complexes were measured in different solvents and ionic strength.The transfection effi-ciency in HepG2 cells was observed.Results: There was a positive correlation between combination of PEI and DNA and molecule weight of PEI.In addition,the surface properties of PEI/DNA complexes were also influenced by the solvents and ionic strength.Comparable transfection efficiencies in HepG2 cells were observed for the Lipo-fectamine 2000/DNA and the prepared PEI(25 kD)/DNA complexes in PBS at the N/P ratio of 12-15,which was much higher than that of naked DNA.Conclusion: The optimized PEI/DNA complexes could effeciently transfect the cells in comparison to the positive control.
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OBJECTIVE:To optimize the formula of compound xylocaine cream.METHODS:Orthogonal design was employed to optimize the amount of each component in the formula of compound xylocaine cream,and the pain threshold improvement rate in pain-relieving experiment of mice and the mice ear edema inhibition rate in the anti-inflammatory experiment served as indexes to optimize the formula,meanwhile a verification test was conducted.RESULTS:The optimized formula was as follows:xylocaine 20 g,chlorphenamine maleate 5 g,menthol 20 g,mupirocin 20 g in every 1 000 g cream.Both the pain threshold improvement rate and the ear edema inhibition rate in mice were all higher than 60%,which were up to the standard.CONCLUSION:The formula for compound xylocaine cream is reasonable,and this study provids experimental basis for clinical application of compound xylocaine cream.
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OBJECTIVE: To optimize the formula of retinoid self-emulsifying preparation. METHODS: The formula of retinoid self-emulsifying drug delivery system was optimized with the solubility of retinoid in different kinds/proportions of oil phases and surfactants as index through solubility test and drawing of ternary phase diagrams. RESULTS: The optimized formula ratio of retinoid self-emulsifying preparation was 0.01∶0.938∶0.402∶0.15 (retinoid / IPM/ Tween-85/ isopropanol, g∶g∶g∶mL). CONCLUSION: The retinoid self-emulsifying preparation prepared in accordance with the above-mentioned ratio is up to the related standard.