This study investigated the formulation mechanism of microspheres via internal surfactant distribution. Eudragit L100 based microspheres loaded with bovine serum albumin were prepared by solid in oil in oil emulsion s...This study investigated the formulation mechanism of microspheres via internal surfactant distribution. Eudragit L100 based microspheres loaded with bovine serum albumin were prepared by solid in oil in oil emulsion solvent evaporation method using acetone and liquid paraffin system containing sucrose stearate as a surfactant. The fabricated microspheres were evaluated for encapsulation efficiency, particle size, production yield, and in vitro release characteristics. The internal structures of microspheres were characterized using synchrotron radiation X-ray microcomputed tomography(SR-μCT). The enhanced contrast made the sucrose stearate distinguished from Eudragit to have its three dimensional(3D) distribution. Results indicated that the content and concentration determined the state of sucrose stearate and had significant influences on the release kinetics of protein. The dispersity of sucrose stearate was the primary factor that controlled the structure of the microspheres and further affected the encapsulation efficiency, effective drug loading, as well as in vitro release behavior. In conclusion, the 3D internal distribution of surfactant in microspheres and its effects on protein release behaviors have been revealed for the first time. The highly resolved 3D architecture provides new evidence for the deep understanding of the microsphere formation mechanism.展开更多
It is essential to develop effective methods for the quality control of the traditional medicine with multiple components.However,few researches on the quality control have been conducted to interpret the holistic cha...It is essential to develop effective methods for the quality control of the traditional medicine with multiple components.However,few researches on the quality control have been conducted to interpret the holistic characteristics of the traditional medicine in terms of dissolution/release.In this study,the multi-component release kinetics of Traditional Chinese Medicine(TCM)dosage forms was characterized and mapped by multivariate analysis techniques in the field of‘‘-omics’’.The Liuweidihuang pill was used as a model formulation.The multi-component release kinetics of the concentrated and water-honeyed Liuweidihuang pills at rotation speeds of 50 and 100 rpm were analyzed by chemomic release kinetic theory and modified LC/MS/MS method.Mass features of 103(concentrated pills)and 101(water-honeyed pills)were selected with a linear correlation coefficient Z0.99 between mass responses and concentrations.To compose the chemomic standard spectrum,the relative abundance of both mass features was no less than 1%as compared with an internal standard.The correlation coefficients between six samples of various solutions were in line with analytical requirements of precision(rZ0.985).The score plots of principal component analysis showed that the concentrated Liuweidihuang pills presented better chemomic release reproducibility than the water-honeyed pills.Conversely,the impact of rotation speed on the chemomic release was less obvious.The heat maps of hierarchical clustering analysis did not show significant changes in individual clusters of mass features along different time intervals,reflecting the release integrity of the mass features.Therefore,both multivariate analysis methods,the principal component analysis and the hierarchical clustering analysis,seemed to be effective techniques to demonstrate the multiple component release performance of TCM.The research provided the basis of a new strategy for the quality control procedures of the dissolution/release for the traditional medicine and multi-component natural products to address increasing regulatory requirements and scrutiny across the world.展开更多
Defining and visualizing the three-dimensional(3 D) structures of pharmaceuticals provides a new and important tool to elucidate the phenomenal behavior and underlying mechanisms of drug delivery systems. The mechanis...Defining and visualizing the three-dimensional(3 D) structures of pharmaceuticals provides a new and important tool to elucidate the phenomenal behavior and underlying mechanisms of drug delivery systems. The mechanism of drug release from complex structured dosage forms, such as bilayer osmotic pump tablets, has not been investigated widely for most solid 3 D structures. In this study, bilayer osmotic pump tablets undergoing dissolution, as well as after dissolution in a desiccated solid state were examined, and visualized by synchrotron radiation micro-computed tomography(SR-μCT). In situ formed 3 D structures at different in vitro drug release states were characterized comprehensively. A distinct movement pattern of NaCl crystals from the push layer to the drug layer was observed, beneath the semi-permeable coating in the desiccated tablet samples. The 3 D structures at different dissolution time revealed that the pushing upsurge in the bilayer osmotic pump tablet was directed via peripheral“roadways”. Typically, different regions of the osmotic front, infiltration region, and dormant region were classified in the push layer during the dissolution of drug from tablet samples. According to the observed3 D microstructures, a “subterranean river model” for the drug release mechanism has been defined to explain the drug release mechanism.展开更多
Changes in structure of oral solid dosage forms(OSDF)elementally determine the drug release and its therapeutic effects.In this research,synchrotron radiation X-ray micro-computed tomography was utilized to visualize ...Changes in structure of oral solid dosage forms(OSDF)elementally determine the drug release and its therapeutic effects.In this research,synchrotron radiation X-ray micro-computed tomography was utilized to visualize the 3 D structure of enteric coated pellets recovered from the gastrointestinal tract of rats.The structures of pellets in solid state and in vitro compendium media were measured.Pellets in vivo underwent morphological and structural changes which differed significantly from those in vitro compendium media.Thus,optimizations of the dissolution media were performed to mimic the appropriate in vivo conditions by introducing pepsin and glass microspheres in media.The sphericity,pellet volume,pore volume and porosity of the in vivo esomeprazole magnesium pellets in stomach for2 h were recorded 0.47,1.55×10^(8)μm^(3),0.44×10^(8)μm^(3)and 27.6%,respectively.After adding pepsin and glass microspheres,the above parameters in vitro reached to 0.44,1.64×10^(8)μm^(3)0.38×10^(8)μm^(3)and 23.0%,respectively.Omeprazole magnesium pellets behaved similarly.The structural features of pellets between in vitro media and in vivo condition were bridged successfully in terms of 3 D structures to ensure better design,characterization and quality control of advanced OSDF.展开更多
The secretion of melatonin(MT)is obviously different in the younger and the senior sectors of the population,and the maximum plasma concentration of seniors is only half of that in the younger population group.If exog...The secretion of melatonin(MT)is obviously different in the younger and the senior sectors of the population,and the maximum plasma concentration of seniors is only half of that in the younger population group.If exogenous MT can be supplied to senior citizens based on the secretion rate and amount of endogenous MT in the younger population by a bio-mimetic drug delivery system(DDS),an improved therapeutic effect and reduced side effects can be expected.Based upon this hypothesis,the pharmacokinetic parameters of MT,namely,the absorption rate constant(ka),the elimination rate constant(ke),and the ratio of absorption rate(F)to the apparent volume of distribution(V)were obtained by a residual method depending on the plasma concentration curve of immediate release preparations in the healthy younger population.The dose-division method was applied to calculate the cumulative release profiles of MT achieved by oral administration of a controlled release drug delivery system(DDS)to generate plasma MT profiles similar to the physiological level-time profiles.The in vivo release of MT deduced from the healthy younger population physiological MT profiles as the pharmacokinetic output of the bio-mimetic DDS showed a two-phase profile with two different zero order release rates,namely,4.919μg/h during 0-4 h(r=0.9992),and 11.097μg/h during 4-12 h(r=0.9886),respectively.Since the osmotic pump type of DDS generally exhibits a good correlation between in vivo and in vitro release behaviors,an osmotic pump controlled delivery system was designed in combination with dry coating technology targeting on the cumulative release characteristics to mimic the physiological MT profiles in the healthy younger population.The high similarity between the experimental drug release profiles and the theoretical profiles(similarity factor f_(2)>50)and the high correlation between the predicted plasma concentration profiles and the theoretical plasma concentration profiles(r=0.9366,0.9163,0.9264)indicated that a prototype bio-mimetic drug delivery system of MT was established.The similarity factors between the experimental drug release profiles and the theoretical release profile were all larger than 50 both in periods of 0-4 h and 4-12 h,namely,68.8 and 57.3 for the first batch(Batch No.20131031),76.7 and 50.2 for the second batch(Batch No.20131101),and 73.7 and 51.1 for the third batch(Batch No.20131126),respectively.The correlation coefficients between the predicted plasma concentration profiles based on the release profiles of the bio-mimetic DDS and physiological profiles were 0.9366(Batch No.20131031),0.9163(Batch No.20131101),0.9264(Batch No.20131126),respectively.Since the pharmacokinetic profile of MT in any kind of animal differs markedly from that of human beings,it is impossible to test the bio-mimetic DDS in animals directly.Therefore,the predicted pharmacokinetic profile based upon the in vitro release kinetics is an acceptable surrogate for the conventional animal test.In this research,a bio-mimetic DDS for replacement of MT was designed with in silico evaluation.展开更多
基金the financial support from the National Natural Science Foundation of China(No.81430087)the National Science and Technology Major Project(2013ZX09402103)
文摘This study investigated the formulation mechanism of microspheres via internal surfactant distribution. Eudragit L100 based microspheres loaded with bovine serum albumin were prepared by solid in oil in oil emulsion solvent evaporation method using acetone and liquid paraffin system containing sucrose stearate as a surfactant. The fabricated microspheres were evaluated for encapsulation efficiency, particle size, production yield, and in vitro release characteristics. The internal structures of microspheres were characterized using synchrotron radiation X-ray microcomputed tomography(SR-μCT). The enhanced contrast made the sucrose stearate distinguished from Eudragit to have its three dimensional(3D) distribution. Results indicated that the content and concentration determined the state of sucrose stearate and had significant influences on the release kinetics of protein. The dispersity of sucrose stearate was the primary factor that controlled the structure of the microspheres and further affected the encapsulation efficiency, effective drug loading, as well as in vitro release behavior. In conclusion, the 3D internal distribution of surfactant in microspheres and its effects on protein release behaviors have been revealed for the first time. The highly resolved 3D architecture provides new evidence for the deep understanding of the microsphere formation mechanism.
基金This work was supported by the Shanghai Science and Technology Development Funds(No.09dZ1973300)Key Projects in the National Science&Technology Pillar Program(No.2009ZX09304-003).
文摘It is essential to develop effective methods for the quality control of the traditional medicine with multiple components.However,few researches on the quality control have been conducted to interpret the holistic characteristics of the traditional medicine in terms of dissolution/release.In this study,the multi-component release kinetics of Traditional Chinese Medicine(TCM)dosage forms was characterized and mapped by multivariate analysis techniques in the field of‘‘-omics’’.The Liuweidihuang pill was used as a model formulation.The multi-component release kinetics of the concentrated and water-honeyed Liuweidihuang pills at rotation speeds of 50 and 100 rpm were analyzed by chemomic release kinetic theory and modified LC/MS/MS method.Mass features of 103(concentrated pills)and 101(water-honeyed pills)were selected with a linear correlation coefficient Z0.99 between mass responses and concentrations.To compose the chemomic standard spectrum,the relative abundance of both mass features was no less than 1%as compared with an internal standard.The correlation coefficients between six samples of various solutions were in line with analytical requirements of precision(rZ0.985).The score plots of principal component analysis showed that the concentrated Liuweidihuang pills presented better chemomic release reproducibility than the water-honeyed pills.Conversely,the impact of rotation speed on the chemomic release was less obvious.The heat maps of hierarchical clustering analysis did not show significant changes in individual clusters of mass features along different time intervals,reflecting the release integrity of the mass features.Therefore,both multivariate analysis methods,the principal component analysis and the hierarchical clustering analysis,seemed to be effective techniques to demonstrate the multiple component release performance of TCM.The research provided the basis of a new strategy for the quality control procedures of the dissolution/release for the traditional medicine and multi-component natural products to address increasing regulatory requirements and scrutiny across the world.
基金the National Nature Science Foundation of China (Nos.81803446,81803441 and 81773645)Key Program for International Science and Technology Cooperation Projects of China (2020YFE0201700)the Youth Innovation Promotion Association of CAS (2018323)。
文摘Defining and visualizing the three-dimensional(3 D) structures of pharmaceuticals provides a new and important tool to elucidate the phenomenal behavior and underlying mechanisms of drug delivery systems. The mechanism of drug release from complex structured dosage forms, such as bilayer osmotic pump tablets, has not been investigated widely for most solid 3 D structures. In this study, bilayer osmotic pump tablets undergoing dissolution, as well as after dissolution in a desiccated solid state were examined, and visualized by synchrotron radiation micro-computed tomography(SR-μCT). In situ formed 3 D structures at different in vitro drug release states were characterized comprehensively. A distinct movement pattern of NaCl crystals from the push layer to the drug layer was observed, beneath the semi-permeable coating in the desiccated tablet samples. The 3 D structures at different dissolution time revealed that the pushing upsurge in the bilayer osmotic pump tablet was directed via peripheral“roadways”. Typically, different regions of the osmotic front, infiltration region, and dormant region were classified in the push layer during the dissolution of drug from tablet samples. According to the observed3 D microstructures, a “subterranean river model” for the drug release mechanism has been defined to explain the drug release mechanism.
基金financial support from National Key R&D Program of China(2020YFE0201700)Major New Drugs Innovation and Development(2017ZX09101001-005,China)+1 种基金the National Natural Science Foundation of China(81803441,81803446 and 81773645)Youth Innovation Promotion Association CAS(2018323,China)。
文摘Changes in structure of oral solid dosage forms(OSDF)elementally determine the drug release and its therapeutic effects.In this research,synchrotron radiation X-ray micro-computed tomography was utilized to visualize the 3 D structure of enteric coated pellets recovered from the gastrointestinal tract of rats.The structures of pellets in solid state and in vitro compendium media were measured.Pellets in vivo underwent morphological and structural changes which differed significantly from those in vitro compendium media.Thus,optimizations of the dissolution media were performed to mimic the appropriate in vivo conditions by introducing pepsin and glass microspheres in media.The sphericity,pellet volume,pore volume and porosity of the in vivo esomeprazole magnesium pellets in stomach for2 h were recorded 0.47,1.55×10^(8)μm^(3),0.44×10^(8)μm^(3)and 27.6%,respectively.After adding pepsin and glass microspheres,the above parameters in vitro reached to 0.44,1.64×10^(8)μm^(3)0.38×10^(8)μm^(3)and 23.0%,respectively.Omeprazole magnesium pellets behaved similarly.The structural features of pellets between in vitro media and in vivo condition were bridged successfully in terms of 3 D structures to ensure better design,characterization and quality control of advanced OSDF.
基金This work was supported from the National Science and Technol-ogy Major Project of the Ministry of Science and Technology of China(2010ZX09401-402)the Chinese Academy of Sciences Visiting Professorship for Senior International Scientists(Prof.Peter York,2013).
文摘The secretion of melatonin(MT)is obviously different in the younger and the senior sectors of the population,and the maximum plasma concentration of seniors is only half of that in the younger population group.If exogenous MT can be supplied to senior citizens based on the secretion rate and amount of endogenous MT in the younger population by a bio-mimetic drug delivery system(DDS),an improved therapeutic effect and reduced side effects can be expected.Based upon this hypothesis,the pharmacokinetic parameters of MT,namely,the absorption rate constant(ka),the elimination rate constant(ke),and the ratio of absorption rate(F)to the apparent volume of distribution(V)were obtained by a residual method depending on the plasma concentration curve of immediate release preparations in the healthy younger population.The dose-division method was applied to calculate the cumulative release profiles of MT achieved by oral administration of a controlled release drug delivery system(DDS)to generate plasma MT profiles similar to the physiological level-time profiles.The in vivo release of MT deduced from the healthy younger population physiological MT profiles as the pharmacokinetic output of the bio-mimetic DDS showed a two-phase profile with two different zero order release rates,namely,4.919μg/h during 0-4 h(r=0.9992),and 11.097μg/h during 4-12 h(r=0.9886),respectively.Since the osmotic pump type of DDS generally exhibits a good correlation between in vivo and in vitro release behaviors,an osmotic pump controlled delivery system was designed in combination with dry coating technology targeting on the cumulative release characteristics to mimic the physiological MT profiles in the healthy younger population.The high similarity between the experimental drug release profiles and the theoretical profiles(similarity factor f_(2)>50)and the high correlation between the predicted plasma concentration profiles and the theoretical plasma concentration profiles(r=0.9366,0.9163,0.9264)indicated that a prototype bio-mimetic drug delivery system of MT was established.The similarity factors between the experimental drug release profiles and the theoretical release profile were all larger than 50 both in periods of 0-4 h and 4-12 h,namely,68.8 and 57.3 for the first batch(Batch No.20131031),76.7 and 50.2 for the second batch(Batch No.20131101),and 73.7 and 51.1 for the third batch(Batch No.20131126),respectively.The correlation coefficients between the predicted plasma concentration profiles based on the release profiles of the bio-mimetic DDS and physiological profiles were 0.9366(Batch No.20131031),0.9163(Batch No.20131101),0.9264(Batch No.20131126),respectively.Since the pharmacokinetic profile of MT in any kind of animal differs markedly from that of human beings,it is impossible to test the bio-mimetic DDS in animals directly.Therefore,the predicted pharmacokinetic profile based upon the in vitro release kinetics is an acceptable surrogate for the conventional animal test.In this research,a bio-mimetic DDS for replacement of MT was designed with in silico evaluation.
