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Objective: To reduce or avoid the volatilization loss of camphor (CA) in the industrialized preparation of cataplasm, using the inclusion technology of HP-β-CD. Methods: The HP-β-CD inclusion compound of CA (CA-HP-β-CD) was prepared by the constant temperature stirring method. The preparation processing of CA-HP-β-CD was optimized with inclusion efficiency as an index, and the pharmaceutical properties of CA-HP-β-CD were characterized by DSC, UV and SEM. The CA and CA-HP-β-CD were prepared to cataplasm at the industrial-scale production respectively, then the content of CA was determined and the statistical analysis was carried out. Results: The inclusion efficiency of CA-HP-β-CD for CA was (68.57 ± 1.26)% when the CA-HP-β-CD was prepared with the mass ratio of CA to HP-β-CD 1:3, the working temperature at 35 ℃ and stirring at 300 r/min for 4.0 h. The DSC, UV and SEM scans showed that there was a good compatibility between CA and HP-β-CD, and CA could be fully encapsulated by HP-β-CD and formed a stable inclusion complex of CA-HP-β-CD. Results of industrial-scale production of cataplasm for CA and CA-HP-β-CD revealed that the retention rate (actual content/feeding quantity) were (80.13 ± 1.05)% and (39.45 ± 1.38)%, respectively. And there was a statistically significant difference between them (t-test, P < 0.01), indicating that the HP-β-CD inclusion complex effectively reduce the volatilization loss of camphor CA. Conclusion: The volatilization loss of CA at the industrial-scale production of cataplasm was effectively reduced by the CA-HP-β-CD, which improves the utilization rate of CA and reduces the cost, and provides ideas and reference for the research and development of cataplasm of volatile drugs.
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Objective: To synthetize the new-type GO-DEX-β-CD/DOC and Fe3O4/GO-Na/DOC inclusion compound, and study its high-efficiency loading, sustained-release and permeability as transdermal delivery for docetaxel (DOC) composites. Methods: The concentration of DOC was determined by high efficiency liquid chromatography. The high-efficiency loading, sustained-release and permeability as transdermal delivery of GO-DEX-β-CD/DOC and Fe3O4/GO-Na/DOC were studied, and the encapsulation efficiency and drug loading of them were determined by centrifugation. The GO-DEX-β-CD/DOC and Fe3O4/GO-Na/DOC were applied onto the female mice skin in vitro and in vivo to develop the permeability of them. Results: The encapsulation efficiency and drug loading of Fe3O4/GO-Na/DOC were higher than GO-DEX-β-CD/DOC, and its slow release property and permeability as transdermal delivery were better. The results showed that the accumulation permeation amount was (22.512 ± 0.715) μg after Fe3O4/GO-Na/DOC being applied over 90 h, DOC concentration in skin reached a peak at 15 min by the application of Fe3O4/GO-Na/DOC. After 5 h of administration, DOC concentration in the blood of female mice reached (76.886 ± 1.232) μg/mL. Conclusion: The preparation techniques of Fe3O4/GO-Na/DOC was feasible with better sustained release and transdermal effect, which had a promising application prospect.
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Objective: The inclusion compound of silymarin-SBE-β-CD was prepared. Methods: Phase solubility method was used to screen the inclusion materials of cyclodextrin and determine the type of inclusion. The technological conditions of silymarin inclusion complex were optimized by orthogonal design. The solubility of inclusion was determined and its structure was characterized by means of microscope, infrared spectrum analysis and X-ray diffraction analysis. Results: Due to its higher solubilization effect on silymarin, SBE-β-CD was determined as inclusion material. The ratio of drug to cyclodextrin was coated in the mode of 1:n. The process optimized by orthogonal design was as follow: molar ratio of silymarin to SBE-β-CD of 1:8, inclusion temperature of 60 ℃, and inclusion time of 3 h. Microscope, infrared spectrum analysis and X-ray diffraction analysis showed that the inclusion compound was formed and the drug existed in the inclusion compound as amorphous. Conclusion: The inclusion compound of silymarin-SBE-β-CD has been successfully prepared, which can significantly improve the solubility of the drug, and provide experimental basis for its clinical application.
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AIM To compare the effects of three preparation technologies on the oral bioavailability of HB (berberine α-hydroxy β-decanoylethyl sulfonate,houttuyn berberine).METHODS Solid dispersions,HP-β-CD inclusion complexes and nanosuspension freeze-dried powders were prepared.The suspensions of crude drug and these three preparations were intragastrically administered to SD rats,respectively.HPLC-MS/MS was adopted in the content determination of HB in plasma.then pharmacokinetics parameters were calculated.RESULTS Compared with the crude drug,three preparation technologies could significantly increase the Cmax value of this component (P ＜ 0.05),especially for HP-β-CD inclusion complexes (P ＜ 0.01).And HP-β-CD inclusion complexes demonstrated much higher AUC0-6h than the crude drug and the other two preparation technologies (P ＜ 0.05).CONCLUSION HP-β-CD inclusion complexes can effectively increase the oral bioavailability of HB.
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Objective To optimize ambi-extracting and inclusion process of volatile oil from Chuanxiong Rhizoma and Angelicae Sinensis Radix. Methods With yield ratio of volatile oil and ferulic acid content in water extract as evaluation indexes, single factor experiments were used to study the extraction process. With the inclusion rate of volatile oil and yield of inclusion as evaluation indexes, saturated aqueous solution was used to L9(34) orthogonal experiments to reach optimum inclusion process. Results The optimum extraction process of Chuanxiong Rhizoma and Angelicae Sinensis Radix was extracted for 8 hours with 8 folds the amount of water, and without soaking. The validation experiments of extraction of volatile oil and ferulic acid content in water extract were 1.23 mL and 0.387 9 mg/g. The optimum conditions of inclusion process were as follows: volatile oil (mL): β-CD (g) was 1:8;inclusion temperature was 40 ℃; inclusion time was 3 hours. The validation experiments of inclusion rate of volatile oil and yield of inclusion were 74.89% and 72.81%. Conclusion Optimum ambi-extracting and inclusion process of volatile oil from Chuanxiong Rhizoma and Angelicae Sinensis Radix are feasible and stable, witch can provide certain supporting data for preparation production.
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Objective To investigate the effects and the law of anti bitterness efficiency of hydroxypropyl-β-cyclodextrin (HP-β-CD) and other different types bitterness masking at different concentrations on the bitterness decoction of Chinese materia medica (BDCMM) by using the traditional human taste panel method (THTPM) and Electronic tongue (E-tongue). Methods Based on THTPM, the bitterness reduction value (ΔI), the correction rate of bitterness suppression (CRBS), and the correction rate of bitterness suppression potency index (PI50) were used as indicators to evaluate the bitterness suppression effect of four bitterness masking at different concentrations on BDCMM such as Sophorae Flavescentis Radix (SFR), and the relationship model between the concentrations of ΔI and bitterness masking was established to explore the bitterness suppression rule of bitterness masking on different BDCMM. Based on the E-tongue method, the E-tongue taste response information values of HP-β-CD and Acesulfame K to BDCMM such as SFR were measured at different concentrations, and the electronic tongue bitterness reduction value (ΔIe) was used as an index to explore the change rule of ΔIe with bitterness masking concentration. THTPM and E-tongue was combined to establish a prediction model of the effect of bitterness suppression. Results The ΔI, CRBS, and PI50 of four kinds of BDCMM with different concentrations of bitterness masking were measured, which can be used to compare the bitterness suppression effect of bitterness masking; The relation between ΔI and bitterness masking concentration accorded with Weibull curve model; Based on E-tongue, ΔIe was obtained, and the model of the relationship between ΔIe and bitterness masking concentration was established. The relationship between ΔIe and ΔI was established. The model determination coefficients of HP-β-CD for the two types of ΔIe of the two BDCMM were 0.986 1, 0.977 9, 0.989 0, and 0.982 0 respectively (P < 0.01, n = 6). Acesulfame had no response to the sensor and did not establish a model of bitterness suppression law. Conclusion Based on THTPM and E-tongue, a method for evaluating the bitterness suppression effect of bitterness masking on BDCMM was established. The bitterness suppression effect of bitterness masking on BDCMM such as SFR was studied by molecular inclusion, high-efficiency sweetening, and other bitterness suppression mechanisms were inverstigated.
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OBJECTIVE: To prepare inclusion complex of SBE7-β-CD with trimethoprim(TMP) and optimize the preparation process, to evaluate the products by structural characterization and molecular simulation. METHODS: The TMP/SBE7-β-CD inclusion complex was prepared by the ultrasound-freeze-dry method and the preparation process was optimized by Box-Behnken Design-response surface method(BBD-RSM). Inclusion complex was characterized by FT-IR, DSC, XRPD and 1H-NMR. Molecular docking method was used to simulate 3-dimensional conformations of the inclusion complex and the binding energy was calculated. The dissolution and stability were tested. RESULTS: The optimum conditions of TMP/SBE7-β-CD inclusion complex were: temperature(52 ℃), time(45 min), and the ratio of SBE7-β-CD and TMP(mol/mol, 1.7∶1). All characterizations(FT-IR, DSC, XRPD and 1H-NMR) indicated the formation of TMP/SBE7-β-CD inclusion complex. The best 3-dimensional docking conformation was consistent with the characterizations, and the binding energy was -9.015 kcal·mol-1. The TMP dissolution rate of the inclusion complex increased significantly, the hygroscopicity is strong. CONCLUSION: The preparation process of TMP/SBE7-β-CD inclusion complex optimized by BBD-RSM is reasonable and feasible. The characterizations of inclusion complex are reliable. The molecular simulation is corresponded to the characterized results and provided reliable theoretical basis for inclusion experiments.
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In this paper, tanshinone-ⅡA (Tan-IIA)/β-cyclodextrin (β-CD) inclusion complexes were prepared by saturated aqueous solution method. Based on the single factor experiment, Box-Benhnken design and response surface method were utilized to optimize the preparation procedures of tanshinone-ⅡA/β-cyclodextrin inclusion complexes. The ratio of β-CD to Tan-ⅡA, experimental temperature and time were defined as independent variables, while the yield of the inclusion complexes, encapsulation efficiency and the generalized "normalized value" were set as the response value. In addition, the inclusion complexes were characterized by infrared spectroscopy (IR) and nuclear magnetic resonance (NMR). The results showed that optimum preparation conditions for Tan-ⅡA/β-CD inclusion complex were as follows: Tan-ⅡA/β-CD ratio of 1:7, the temperature of 48 ℃ and the time of 3 h. Under the optimized conditions, the encapsulation efficiency of Tan-ⅡA/β-CD inclusion complex was 84.75%. The Tan-IIA and β-CD inclusion complex can significantly improve the dissolution of Tan-ⅡA.
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Objective To optimize the processes of extraction and inclusion of volatile oil from Citri Grandis Exocarpium. Methods With yield ratio of volatile oil as evaluation index, single factor experiments were used to study the extraction process of volatile oil. With the inclusion rate of the volatile oil and the yield of inclusion as evaluation indexes, saturated aqueous solution was used to the L9(34) orthogonal experiments to reach the best inclusion process optimization. And the microscopic imaging analysis and X-ray scattering technology were adopted to character the inclusion compound. Results The optimum extraction process of volatile oil was extracted for 10 hours with 10 folds the amount of water, and without soaking. The optimum conditions of inclusion process were as follows: volatile oil (mL): β-CD (g): water (mL) ratio was 1:8:80; inclusion temperature was 50 ℃; inclusion time was 3 hour. The validation experiments of the inclusion rate of the volatile oil and the yield of inclusion were 91.50% and 88.36%. Microscopic imaging analysis and X-ray scattering technology proved the inclusion compound had been formed. Conclusion Optimal extraction and inclusion process are feasible and stable, which can provide certain supporting data for preparation and production.
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OBJECTIVE:To prepare paeonol-HP-β-cyclodextrin (PAE-HP-β-CD) inclusion compound and to optimize its pre-scription technology. METHODS:PAE-HP-β-CD was prepared by freeze drying method and validated. Using inclusion rate as in-dex,main drug-accessory ratio,inclusion time,inclusion temperature and stirring speed as factors,the preparation technology was optimized by central composite design-response surface methodology. RESULTS:Prepared PAE-HP-β-CD underwent phase transfor-mation. The optimal inclusion technology was as follows as main drug-accessory ratio of 3.39∶1,inclusion temperature of 50 ℃, inclusion time of 3.2 h, stirring speed of 350 r/min. Relative error between measured value (87.46%) and predicted value (89.12%) of inclusion rate was 1.86%(n=6). CONCLUSIONS:PAE-HP-β-CD inclusion compound is prepared successfully, and its prescription technology is stable and feasible.
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Objective To study the bitterness inhibition law of hydroxypropyl-β-cyclodextrin (HP-β-CD) concentration (C) on the bitter compounds and bitter Chinese herbal medicine, and to explore the application of electronic tongue in this study. Methods Berberine, oxymatrine, Sophora flavescens, and Andrographis paniculata decoction were used as bitterness vectors to establish two models of bitterness inhibition law about ΔI-C and ΔIe-C, and to explore the prediction model of bitterness inhibition effect about ΔI-ΔIe, based on the oral taste evaluation results (ΔI) and electronic tongue information (ΔIe). Then, fitting precision and fitting goodness of the prediction model were evaluated with cross-validation and residual analysis. Results In this study, good Weibull model of bitterness inhibition pattern about ΔI-C were established for all the four bitterness vectors, the decision coefficient R2 are as followed: 0.999 6, 0.987 9, 0.996 4, and 0.998 4 (P < 0.01); The decision coefficient R2 of six (two sensors per vector) models of bitterness inhibition law about ΔIe-C of berberine, S. flavescens, and A. paniculata decoctions were as followed: 0.996 5, 0.991 6, 0.997 3, 0.989 3, 0.999 6, and 0.999 1 (P < 0.01); The decision coefficient R2 of six corresponding linear prediction models of bitterness inhibition effect about ΔI-ΔIe were as followed: 0.989 1, 0.968 3, 0.989 0, 0.982 0, 0.977 9, and 0.986 1 (P < 0.01); The correlation coefficient R calculated by correlation coefficient of six prediction models above were as followed: 0.986 0, 0.997 3, 0.988 4, 0.960 8, 0.980 2, and 0.983 9 (P < 0.01); No model was established for oxymatrine within the range of tested concentration in this research, as it didn’t respond to the four sensors with varied concentration. Conclusion Based on this method, the bitterness inhibition law of HP-β-CD with changed concentration was obtained. Prediction models based on HP-β-CD concentration or electronic tongue data were also established, they can be used to predict the relative bitterness inhibition effect. Part of the bitter compounds didn't response to the electronic tongue regularly, remain further research and development of electronic tongue technology.
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Objective To optimize the processes of extraction and inclusion of volatile oil from Citri Grandis Exocarpium. Methods With yield ratio of volatile oil as evaluation index, single factor experiments were used to study the extraction process of volatile oil. With the inclusion rate of the volatile oil and the yield of inclusion as evaluation indexes, saturated aqueous solution was used to the L9(34) orthogonal experiments to reach the best inclusion process optimization. And the microscopic imaging analysis and X-ray scattering technology were adopted to character the inclusion compound. Results The optimum extraction process of volatile oil was extracted for 10 hours with 10 folds the amount of water, and without soaking. The optimum conditions of inclusion process were as follows: volatile oil (mL): β-CD (g): water (mL) ratio was 1:8:80; inclusion temperature was 50 ℃; inclusion time was 3 hour. The validation experiments of the inclusion rate of the volatile oil and the yield of inclusion were 91.50% and 88.36%. Microscopic imaging analysis and X-ray scattering technology proved the inclusion compound had been formed. Conclusion Optimal extraction and inclusion process are feasible and stable, which can provide certain supporting data for preparation and production.
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Objective To optimize the preparation of liensinine HP-β-CD inclusion compound; To investigate its dissolution performance in vitro. Methods The inclusion compound of liensinine was prepared by using saturated water solution method; the cumulative dissolution (45 min) was used as an indicator and Box-Behnken design was adopted to evaluate the influence of feed ratio, mixing time and inclusion temperature on preparation process. Results were analyzed by multiple linear and binomial fitting; response surface methodology was used to screen the optimal inclusion process; predictive parsing and verification experiment were conducted; SEM, DSC, IR, and XRD were applied for the structural characterization of inclusion compound of liensinine. Results The optimal preparation process was: HP-β-CD was 4.5 times the amount of liensinine feeding amount; mixing time was 3.7 h; inclusion temperature was 52 ℃. HP-β-CD inclusion compound of liensinine formed. Conclusion Optimal inclusion process is stable and feasible, which can significantly improve the dissolution of liensinine and increase its bioavailability.
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Volatile oils are important active components in traditional Chinese medicine, but their components are complicated and unstable. It is common to use cyclodextrin inclusion technique to improve the stability of volatile oils and make them easier to be prepared. At present, β-cyclodextrin (β-CD) is the most common inclusion material. The evaluation indicators for inclusion technique usually contain the inclusion rate and the oil content in the inclusion compound. However, the articles about the study on selecting inclusion materials for volatile oils were few. In this paper, menthol, the main active ingredient of mint volatile oil, was used as model drug, while β-CD and hydroxypropyl-β-cyclodextrin (HP-β-CD) were used as the inclusion materials. Inclusion equilibrium constant (K), solubilization ratio were investigated, and the results were combined with IR, DSC and TG to verify the formation of inclusion complexes. It turned out that in the range of 0-15 mmol•L⁻¹, the solubility of menthol was increased linearly with the increase of HP-β-CD concentration, with AL-type phase solubility diagram, K=3 188.62 L•mol⁻¹; in the range of 0-12.5 mmol•L⁻¹, the solubility of menthol was increased linearly with the increase of β-CD concentration, K=818.73 L•mol⁻¹. When the concentration was over 12.5 mmol•L⁻¹, the solubility of menthol appeared to be a negative deviation with the increase of β-CD concentration, with AN-type solubility diagram. The above results showed that the inclusion behavior was different between β-CD and HP-β-CD, laying a foundation for further study on inclusion complexes of volatile oil.
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Objective:To prepare thermosensitive liquid suppositories of mesalazine( MSZ) HP-β-CD complex and study the in vitro properties. Methods:Poloxamer 407 (P407) and poloxamer 188 (P188) were used as the thermosensitive polymers to load MSZ HP-β-CD complex to prepare the thermosensitive liquid suppositories. The viscosity, gel strength, bioadhesion,in vitro gel erosion and drug release of MSZ HP-β-CD complex were compared with those of MSZ liquid suppositories. Results: Compared with that of MSZ liquid suppositories, the gel temperature of MSZ HP-β-CD complex liquid suppositories was stable, while the viscosity, gel strength and bioadhesion of MSZ HP-β-CD complex liquid suppositories were increased significantly. The in vitro gel erosion was not affected by MSZ HP-β-CD complex, while the drug release was notably enhanced. The drug release and gel erosion showed a good linear relation-ship. Conclusion:MSZ HP-β-CD complex liquid suppositories show good gel temperature, viscosity, gel erosion and bioadhesion, and the in vitro release rate is faster than that of MSZ liquid suppositories.
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Objective To optimize the extraction process of volatile oil and inclusion preparation of hydroxypropyl-β-cyclodextrin from compoundJinling Sini Siwu Shixiaosan Granules.Methods The orthogonal approach of L9 (34) was applied to investigate the volume of volatile oil extraction by 3 factors to obtain the optimum extraction conditions. With inclusion rate of volatile oil and yield of inclusion compound as comprehensive evaluation indexes, the optimum preparation conditions were discussed. The characterization of this prepared inclusion was analyzed by TLC.Results The optimum extraction conditions were as follows:the crude medicine with medicinal powder was shattered into 20 meshes;8 times the amount of water was added and was extracted for 8 h. The best inclusion conditions were as follows:the proportion of volatile oil to HP-β-CD was 1∶6, with inclusion temperature of 30℃, grinding time of 2 h. Analysis results of TLC showed that stable inclusion compound was formed from volatile oil and HP-β-CD.Conclusion The optimized extraction process and inclusion preparation are with stable quality and high feasibility.
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OBJECTIVE: To improve the solubility of prasugrel in aqueous solution, the solubilization effect of SBE-β-CD and HP-β-CD research on prasugrel.
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Objective:To investigate the effects of various bio-adhesive polymers on bio-adhesive characteristics and release rate of 5-fluorouracil HP-β-CD inclusion complex thermo-sensitive gels. Methods: Bio-adhesive polymer, such as hydroxypropylmethylcellu-lose ( HPMC) , sodium alginate ( SA) , sodium hyaluronat ( HA) ,carbopol and polycarbophil was respectively used to prepare the ther-mo-sensitive gels, and the bio-adhesive force was studied. The phosphate buffer (pH 7. 2) was used and the drug release characteris-tics were studied using dialysis technique. Results: The bio-adhesive force of the gels with 0. 2% polycarbophil was 32. 3 g·ml-1 , and the drug release time was prolonged to 8 h. There was no obvious difference in the dissolution among the gels with the various bio-adhesive polymers. Conclusion:Using 0. 2% polycarbophil as the bio-adhesive polymer, 5-fluorouracil HP-β-CD inclusion complex thermo-sensitive gels show good bio-adhesive force and prolonged drug release characteristics.
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OBJECTIVE: To prepare genistein from genistin-HP-β-CD inclusion complex by enzymic hydrolysis method. METHODS: The method of saturated water solution was applied to prepare genistin-HP-β-CD, then, genistin inclusion complex was transformed into genistein by snailase. Taking the bioconversion rate as the index, different factors were studied to obtain the feasible reaction conditions. An HPLC method was established to compare the bioconversion rates between genistin and genistin-HP-β-CD under the optimum conditions. Hydrolysis product was identified by H-NMR and C-NMR. RESULTS: The optimum reaction conditions were determined just as follows; the reaction medium was acetic acid-sodium acetate buffer solution of pH 5.0, the ratio of snailase; genistin-HP-β-CD was 4:5, and the reaction time was 12 h at 50°C. Under the above mentioned condition, the conversion rate of genistin-HP-β-CD was (90.17±2.40)%, 0.95 times higher than that of the genistin not entrapped with HP-β-CD. CONCLUSION: Preparing genistein by enzymatic hydrolysis method after entrapping genistin with HP-β-CD can significantly shorten the reaction time, and is suitable for industrialization.
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OBJECTIVE: To performe chiral separation of three pharmaceutical racemates collected in Ch. P 2010 containing N-alkyl groups, including verapamil hydrochloride, chlorphenamine maleate, and chloroquine diphosphate by using SBE-β-CD as a mobile-phase additive in an HPLC system. METHODS: The analysis was carried out on an Alltima C18 column. The mobile phase consisted of acetonitrile and a phosphate solution added with SBE-β-CD and NaH2PO4, whose pH value was adjusted to 2.5 by phosphoric acid. The flow rate was set at 0.8 mL · min-1, and the column temperature was 25°C. The UV detection was carried out at 332, 264 and 278 nm, respectively. The effects of different factors on the separation effect were investigated, including CD types (β-CD, HP-β-CD), SBE-β-CD concentration, pH value, oven temperature, and buffer concentration. RESULTS: The established method was able to separate the three racemates and the mechanism had been discussed. CONCLUSION: Three racemates can be separated on C18 column using SBE-β-CD as a chiral mobile phase additive. This method might be applied to separate various types of biologically important enantiomers which have N-alkyl groups in the chemical structure.