The purpose of this study was to evaluate the impact of polystyrene divinylbenzene copolymer HPLC columns on the chromatographic performance of the USP compendial method for doxycycline hyclate. The compendial method ...The purpose of this study was to evaluate the impact of polystyrene divinylbenzene copolymer HPLC columns on the chromatographic performance of the USP compendial method for doxycycline hyclate. The compendial method was implemented based on the assessment of the chromatographic performance of six USP defined L21 polystyrene divinylbenzene HPLC columns. Modifications to the method were based on USP for chromatography. The method was validated for the determination of doxycycline hyclate and its impurities in commercially available drug products. A number of different polystyrene-divinylbenzene columns were tested and failed to provide selectivity for the resolution of doxycycline and its impurities. Separation was optimally achieved on an Agilent PLPR-S column (250 × 4.6 mm, 8 μm) by using an Agilent 1260 series HPLC system. Doxycycline hyclate and its impurities were eluted isocratically at a flow rate of 1 mL/min with mobile phase and detected at 270 nm. The column temperature was maintained at 60oC. The method was validated according to USP category I requirements for Assay. Validation acceptance criteria were met in all cases. The analytical range for doxycycline hyclate was 50 - 250 μg/mL and the linearity was r2 > 0.999 over three days. The method was determined to be specific. Both accuracy (95.1% - 102.4%) and precision (0.50% - 4.8%) were established across the analytical range for low, intermediate and high QC concentrations. Method applicability was demonstrated by analyzing marketed products of doxycycline hyclate, in which results showed potency meeting USP acceptance criteria. In conclusion, this study described the remarkable differences in selectivity that were encountered during the implementation phase for the compendial methods for doxycycline and its impurities in marketed products and it could be used in the future to assss the product quality of doxycycline hyclate capsules stored in the National stockpiles.展开更多
Amphotericin B(AmB)is an amphiphilic drug commonly formulated in liposomes and administered intravenously to treat systemic fungal infections.Recent studies on the liposomal drug product have shed light on the AmB agg...Amphotericin B(AmB)is an amphiphilic drug commonly formulated in liposomes and administered intravenously to treat systemic fungal infections.Recent studies on the liposomal drug product have shed light on the AmB aggregation status in the bilayer,which heat treatment(curing)modifies.Although toxicity was found related to aggregation status-loose aggregates significantly more toxic than tight aggregates-the precise mechanism linking aggregation and toxicitywas notwell understood.This study directlymeasured drug release rate fromvarious AmB liposomal preparations made with modified curing protocols to evaluate correlations among drug aggregation state,drug release,and in vitro toxicity.UV–Vis spectroscopy of these products detected unique curing-induced changes in the UV spectral features:a∼25nm blue-shift of the main absorption peak(λ_(max))in aqueous buffer and a decrease in the OD_(346)/OD_(322) ratio upon thermal curing,reflecting tighter aggregation.In vitro release testing(IVRT)data showed,by applying and fitting first-order release kinetic models for one or two pools,that curing impacts two significant changes:a 3–5-fold drop in the overall drug release rate and a ten-fold decrease in the ratio between the loosely aggregated and the tightly aggregated,more thermodynamically stable drug pool.The kinetic data thus corroborated the trend independently deduced from the UV–Vis spectral data.The in vitro toxicity assay indicated a decreased toxicity with curing,as shown by the significantly increased concentration,causing half-maximal potassium release(TC50).The data suggest that the release of AmB requires dissociation of the tight complexes within the bilayer and that the reduced toxicity relates to this slower rate of dissociation.This study demonstrates the relationship between AmB aggregation status within the lipid bilayer and drug release(directly measured rate constants),providing a mechanistic link between aggregation status and in vitro toxicity in the liposomal formulations.展开更多
The development and implementation of advanced analytical technologies is essential for extending the expiry for complex drug products stored in the Strategic National Stockpiles. Consequently, a novel Ultra High-Perf...The development and implementation of advanced analytical technologies is essential for extending the expiry for complex drug products stored in the Strategic National Stockpiles. Consequently, a novel Ultra High-Performance Liquid Chromatographic (UHPLC) method has been developed for the analysis of atropine and its respective impurities to support the analytical research platform for auto-injectors. This study is part of a larger research effort to improve the efficiency and broaden the applicability of advanced analytical methods for medical counter-measure medications. The current HPLC compendial methodology for atropine sulfate injection requires an analysis time of 40 minutes for atropine. In comparison, the novel gradient UHPLC method required only 8 minutes to evaluate both atropine and its major pharmaceutical impurities. Improved separation was achieved on a Waters Acquity UHPLC BEH C18 1.7 μm, 2.1 × 100 mm column employing gradient elution of mobile phase solvent A (0.1% H3PO4) and solvent B (0.1% H3PO4, 90% ACN, and 10% H2O). The method was validated according to USP Category I requirements for assay. The daily standard calibration curves were linear over a concentration range from 50 μg/mL to 250 μg/mL with a correlation coefficient of >0.999. The detection limit (LOD) and quantitation limit (LOQ) were 3.9 μg/ml and 13.1 μg/ml, respectively. Resolution results indicate that atropine and the following impurities, degradants and a preservative can also be separated and analyzed using this proposed method: noratropine, 4,4’-di-hy-droxydiphenyl ether, 2,4’-dihydroxydiphenyl ether, 4-bromophenol, 4-hydro-xyatropine, tropic acid, apoatropine HCl, atropic acid, hydroquinone, nitroethane, phenol and catechol. The UHPLC method demonstrated enhanced selectivity and significantly reduced the analysis time when compared with the traditional USP compendial HPLC method. The method was successfully applied to the evaluation of atropine in ATNAA auto-injectors lots from the Strategic National Stockpiles.展开更多
Posted on January 4,2017 by FDA Voice This past year was another successful year for the new drugs program in FDA’s Center for Drug Evaluation and Research(CDER).CDER reviewed and approved 22 novel drugs,most of whic...Posted on January 4,2017 by FDA Voice This past year was another successful year for the new drugs program in FDA’s Center for Drug Evaluation and Research(CDER).CDER reviewed and approved 22 novel drugs,most of which have the potential to add significant clinical展开更多
Posted on September 15,2015 by FDA VoiceIf you personally know 100 people living in the U.S.,chances are that almost 10 will suffer from some form of a rare disease.If that makes it sound like rare diseases are not ac...Posted on September 15,2015 by FDA VoiceIf you personally know 100 people living in the U.S.,chances are that almost 10 will suffer from some form of a rare disease.If that makes it sound like rare diseases are not actually very rare in this country,that’s because there are 7,000 different rare diseases,80%of which are caused by faulty genes.A rare disease is defined展开更多
Bioequivalence studies play an important role in the drug development as well as during the post-approval period for both new drugs and generic drugs. In principle, the goals of these studies are two-fold: (1) serve a...Bioequivalence studies play an important role in the drug development as well as during the post-approval period for both new drugs and generic drugs. In principle, the goals of these studies are two-fold: (1) serve as bridging studies to provide supportive evidence for safety and efficacy of a drug product; and (2) ensure product quality and performance throughout the life time of a drug product in the presence of changes in formulation or manufacturing. Additionally, in the context of generic drugs, the current U.S. regulation dictates that evidence of bioequivalence and pharmaceutical equivalence provides the assurance of therapeutic equivalence, hence interchangeability. The conventional wisdom for bioequivalence studies indicates that the testing is best performed using the most accurate, sensitive, and reproducible approach available for the drug under examination. Accordingly, to date, comparative pharmacokinetic studies have been used in most cases for bioequivalence determination. In vitro tests are seldom utilized while pharmacodynamic studies and clinical trials are employed for locally acting drug products or when drug levels cannot be measured in the blood. This trend, however, is changing with the recent advances in pharmaceutical science and technology. For example, the introduction of the Biopharmaceutics Classification System (BCS) has provided a valuable tool for predicting drug absorption and bioavailability. The rapidly growing knowledge of pharmacogenetics/genomics combined with formulation science may facilitate a better understanding of the potential interplay between pharmaceutical characteristics and biological system in humans. In the future, an enhanced prediction and assessment of bioequivalence may be achieved through the rational design of formulations and use of in vitro, in situ or in silico test methods. Implicit in the inclusion of pharmaceutical equivalence as part of the definition of therapeutic equivalence has been the regulatory objective of achieving ’sameness’ to the greatest extent possible between a generic and innovator product, thereby avoiding unnecessary in vivo human testing. Perceivably, the better the drug substance and product are characterized, the more accurate and precise the determination of pharmaceutical equivalence will be. An increased assurance of pharmaceutical equivalence based on state-of-the-art science and technology may lessen the uncertainty of ’sameness’ in the clinical responses and reduce the burden for requiring in vivo evidence of bioequivalence. Over the last three decades, scientists have worked diligently to develop guidance and recommendations on how to demonstrate bioequivalence and pharmaceutical equivalence (hence therapeutic equivalence). Approaches to establishing any type of equivalence depend on the scientific knowledge and tools available at the time of evaluation. Continuing efforts and research are encouraged to improve the current approaches, and ensure product quality and performance over time for both new and generic drug products.展开更多
Analysis of carcinogenicity data generally involves a trend test across all dose groups and a pairwise comparison of the high dose group with the control. The most commonly used test for a positive trend is the Cochra...Analysis of carcinogenicity data generally involves a trend test across all dose groups and a pairwise comparison of the high dose group with the control. The most commonly used test for a positive trend is the Cochran-Armitage test. This test is asymptotically normal. For the pairwise comparison of the high dose group with the control group, we propose two modifications: the first modification is to apply the test on the data from high dose and control groups after dropping the data from the low and the medium dose groups;the second modification is to adjust the test conditional on data from all dose groups. We compare the power performance of these two modifications for the pairwise comparisons.展开更多
In an effort to promote the availability of safe and effective drugs, the US Food and Drug Administration is developing spectroscopic methods to assess the quality of drugs in the field. Here we report a rapid screeni...In an effort to promote the availability of safe and effective drugs, the US Food and Drug Administration is developing spectroscopic methods to assess the quality of drugs in the field. Here we report a rapid screening classification method for Tamiflu (oseltamivir phosphate) capsules using a portable Raman spectrometer to perform screening on three solid oral dosage strengths of Tamiflu, 30 mg, 45 mg and 75 mg. Tamiflu is an antiviral drug that is stockpiled for use in the event of pandemic influenza outbreak. The qualitative classification methods reported were developed using the Raman spectra of intact capsules. The classification algorithms used were able to reliably distinguish the three dosage strengths of Tamiflu. These qualitative models are validated with additional Tamiflu samples from different batches and simulated counterfeits of Tamiflu. The probability that a test sample belongs to each dosage strength class is calculated, and strict class predictions are used to assign each sample to a particular class. The classification methods reported here enable development of user-independent, field-deployable methods for finished drug products and are able to correctly assign 92% of the validation samples using authentic Tamiflu and 100% of the simulated counterfeits.展开更多
Network toxicology combined with metabonomics is of great significance for the study of the toxic mechanism and prediction of toxicity of traditional Chinese medicines(TCMs).In this study,we reviewed the application o...Network toxicology combined with metabonomics is of great significance for the study of the toxic mechanism and prediction of toxicity of traditional Chinese medicines(TCMs).In this study,we reviewed the application of network toxicology based on LC-MS metabolomics,mainly in the study of toxic components and the toxicity mechanism of TCMs,which provides new ideas and methods for the further study of the toxicity mechanism of TCMs.展开更多
Compared to small molecule process analytical technology (PAT) applications, biotechnology product PAT applications have certain unique challenges and opportunities. Understanding process dynamics of bioreactor cell...Compared to small molecule process analytical technology (PAT) applications, biotechnology product PAT applications have certain unique challenges and opportunities. Understanding process dynamics of bioreactor cell culture process is essential to establish an appropriate process control strategy for biotechnology product PAT applications. Inline spectroscopic techniques for real time monitoring of bioreactor cell culture process have the distinct potential to develop PAT approaches in manufac- turing biotechnology drug products. However, the use of inline Fourier transform infrared (FTIR) spectroscopic techniques for bioreactor cell culture process monitoring has not been reported. In this work, real time inline FTIR Spectroscopy was applied to a lab scale bioreactor mAb IgG3 cell culture fluid biomolecular dynamic model. The technical feasibility of using FTIR Spectroscopy for real time tracking and monitoring four key cell culture metabolites (including glucose, glutamine, lactate, and ammonia) and protein yield at increasing levels of complexity (simple binary system, fully formulated media, actual bioreactor cell culture process) was evaluated via a stepwise approach. The FTIR fingerprints of the key metabolites were identified. The multivariate partial least squares (PLS) calibration models were established to correlate the process FTIR spectra with the concentrations of key metabolites and protein yield of in-process samples, either individually for each metabolite and protein or globally for all four metabolites simultaneously. Applying the 2'ld derivative pre-processing algorithm to the FTIR spectra helps to reduce the number of PLS latent variables needed significantly and thus simplify the interpretation of the PLS models. The validated PLS models show promise in predicting the concentration profiles of glucose, glutamine, lactate, and ammonia and protein yield over the course of the bioreactor cell culture process. Therefore, this work demonstrated the technical feasibility of real time monitoring of the bioreactor cell culture process via FTIR spectroscopy. Its implications for enabling cell culture PAT were discussed.展开更多
Traditional Chinese medicine (TCM) has developed over thousands of years and has accumulated abundant clinical experience, forming a comprehensive and unique medical system. Emerging evidence has begun to illustrate...Traditional Chinese medicine (TCM) has developed over thousands of years and has accumulated abundant clinical experience, forming a comprehensive and unique medical system. Emerging evidence has begun to illustrate TCM as an area of important medical rediscoveries. This review article briefly introduced the concept, significance, and technology of network pharmacology based on network biology and systems biology. It focused on the theoretical system and potential prospect of TCM network applied in TCM research and development including predicting new drug targets, action mechanism, new drug discovery; evaluating pharmacodynamics, pharmacokinetics, safety, toxicology, quality control, and bioinformatics of drugs. We also discussed the opportunities and challenges in the development and application of network pharmacology in the modernization of TCM research.展开更多
Neonates are at increased risk of viral encephalopathies that can result in neurological dysfunction, seizures, permanent disability and even death. The neurological damage results from the combined effect of the viru...Neonates are at increased risk of viral encephalopathies that can result in neurological dysfunction, seizures, permanent disability and even death. The neurological damage results from the combined effect of the virus and the immune response it elicits, thus finding tools to facilitate viral clearance from central nervous system (CNS) while minimizing neuron damage remains a critical challenge. Neonatal mice inoculated intraperitoneally with Tacaribe virus (TCRV) develop seizures, hindlimb paralysis and death within 15 days of inoculation. TCRV localizes to the CNS within days of challenge, primarily infecting astrocytes in the cerebellum and brain stem. We show that infection leads to inflammation, T cell and monocyte infiltration into the cerebellar parenchyma, apoptosis of astrocytes, neuronal degeneration and loss of Purkinje cells. Infiltrating antigen-specific T cells fail to clear the virus but drive the disease, as T-cell-deficient CD3ε KO mice survive TCRV infection with minimal inflammation or clinical manifestations despite no difference in CNS viral loads in comparison with T-cell sufficient mice. CD8+ T cells drive the pathology, which even in the absence of CD4+ T-cell help, infiltrate the parenchyma and mediate the apoptotic loss of cerebellar astrocytes, neurodegeneration and loss of Purkinje cells resulting in loss of balance, paralysis and death. CD4+ T cells are also pathogenic inducing gliosis and inflammation in the cerebellum and cerebrum that are associated with wasting and death several weeks after CD4+ T-cell transfer. These data demonstrate distinct pathogenic effects of CD4+ and CD8+ T cells and identify them as possible therapeutic targets.展开更多
Posted on October 28,2016 by FDA Voice Here at FDA,we work diligently to be part of our nation’s solution to the opioid abuse epidemic.While there is no single solution to this complex problem,we continue to encourag...Posted on October 28,2016 by FDA Voice Here at FDA,we work diligently to be part of our nation’s solution to the opioid abuse epidemic.While there is no single solution to this complex problem,we continue to encourage efforts to develop new opioid formulations with abuse-deterrent properties that make it harder to abuse these powerful medications.展开更多
文摘The purpose of this study was to evaluate the impact of polystyrene divinylbenzene copolymer HPLC columns on the chromatographic performance of the USP compendial method for doxycycline hyclate. The compendial method was implemented based on the assessment of the chromatographic performance of six USP defined L21 polystyrene divinylbenzene HPLC columns. Modifications to the method were based on USP for chromatography. The method was validated for the determination of doxycycline hyclate and its impurities in commercially available drug products. A number of different polystyrene-divinylbenzene columns were tested and failed to provide selectivity for the resolution of doxycycline and its impurities. Separation was optimally achieved on an Agilent PLPR-S column (250 × 4.6 mm, 8 μm) by using an Agilent 1260 series HPLC system. Doxycycline hyclate and its impurities were eluted isocratically at a flow rate of 1 mL/min with mobile phase and detected at 270 nm. The column temperature was maintained at 60oC. The method was validated according to USP category I requirements for Assay. Validation acceptance criteria were met in all cases. The analytical range for doxycycline hyclate was 50 - 250 μg/mL and the linearity was r2 > 0.999 over three days. The method was determined to be specific. Both accuracy (95.1% - 102.4%) and precision (0.50% - 4.8%) were established across the analytical range for low, intermediate and high QC concentrations. Method applicability was demonstrated by analyzing marketed products of doxycycline hyclate, in which results showed potency meeting USP acceptance criteria. In conclusion, this study described the remarkable differences in selectivity that were encountered during the implementation phase for the compendial methods for doxycycline and its impurities in marketed products and it could be used in the future to assss the product quality of doxycycline hyclate capsules stored in the National stockpiles.
基金financially supported by the Offi ce of Research and Standards, Office of Generic Drugs, CDER at the FDA (75F40120C00055)
文摘Amphotericin B(AmB)is an amphiphilic drug commonly formulated in liposomes and administered intravenously to treat systemic fungal infections.Recent studies on the liposomal drug product have shed light on the AmB aggregation status in the bilayer,which heat treatment(curing)modifies.Although toxicity was found related to aggregation status-loose aggregates significantly more toxic than tight aggregates-the precise mechanism linking aggregation and toxicitywas notwell understood.This study directlymeasured drug release rate fromvarious AmB liposomal preparations made with modified curing protocols to evaluate correlations among drug aggregation state,drug release,and in vitro toxicity.UV–Vis spectroscopy of these products detected unique curing-induced changes in the UV spectral features:a∼25nm blue-shift of the main absorption peak(λ_(max))in aqueous buffer and a decrease in the OD_(346)/OD_(322) ratio upon thermal curing,reflecting tighter aggregation.In vitro release testing(IVRT)data showed,by applying and fitting first-order release kinetic models for one or two pools,that curing impacts two significant changes:a 3–5-fold drop in the overall drug release rate and a ten-fold decrease in the ratio between the loosely aggregated and the tightly aggregated,more thermodynamically stable drug pool.The kinetic data thus corroborated the trend independently deduced from the UV–Vis spectral data.The in vitro toxicity assay indicated a decreased toxicity with curing,as shown by the significantly increased concentration,causing half-maximal potassium release(TC50).The data suggest that the release of AmB requires dissociation of the tight complexes within the bilayer and that the reduced toxicity relates to this slower rate of dissociation.This study demonstrates the relationship between AmB aggregation status within the lipid bilayer and drug release(directly measured rate constants),providing a mechanistic link between aggregation status and in vitro toxicity in the liposomal formulations.
文摘The development and implementation of advanced analytical technologies is essential for extending the expiry for complex drug products stored in the Strategic National Stockpiles. Consequently, a novel Ultra High-Performance Liquid Chromatographic (UHPLC) method has been developed for the analysis of atropine and its respective impurities to support the analytical research platform for auto-injectors. This study is part of a larger research effort to improve the efficiency and broaden the applicability of advanced analytical methods for medical counter-measure medications. The current HPLC compendial methodology for atropine sulfate injection requires an analysis time of 40 minutes for atropine. In comparison, the novel gradient UHPLC method required only 8 minutes to evaluate both atropine and its major pharmaceutical impurities. Improved separation was achieved on a Waters Acquity UHPLC BEH C18 1.7 μm, 2.1 × 100 mm column employing gradient elution of mobile phase solvent A (0.1% H3PO4) and solvent B (0.1% H3PO4, 90% ACN, and 10% H2O). The method was validated according to USP Category I requirements for assay. The daily standard calibration curves were linear over a concentration range from 50 μg/mL to 250 μg/mL with a correlation coefficient of >0.999. The detection limit (LOD) and quantitation limit (LOQ) were 3.9 μg/ml and 13.1 μg/ml, respectively. Resolution results indicate that atropine and the following impurities, degradants and a preservative can also be separated and analyzed using this proposed method: noratropine, 4,4’-di-hy-droxydiphenyl ether, 2,4’-dihydroxydiphenyl ether, 4-bromophenol, 4-hydro-xyatropine, tropic acid, apoatropine HCl, atropic acid, hydroquinone, nitroethane, phenol and catechol. The UHPLC method demonstrated enhanced selectivity and significantly reduced the analysis time when compared with the traditional USP compendial HPLC method. The method was successfully applied to the evaluation of atropine in ATNAA auto-injectors lots from the Strategic National Stockpiles.
文摘Posted on January 4,2017 by FDA Voice This past year was another successful year for the new drugs program in FDA’s Center for Drug Evaluation and Research(CDER).CDER reviewed and approved 22 novel drugs,most of which have the potential to add significant clinical
文摘Posted on September 15,2015 by FDA VoiceIf you personally know 100 people living in the U.S.,chances are that almost 10 will suffer from some form of a rare disease.If that makes it sound like rare diseases are not actually very rare in this country,that’s because there are 7,000 different rare diseases,80%of which are caused by faulty genes.A rare disease is defined
文摘Bioequivalence studies play an important role in the drug development as well as during the post-approval period for both new drugs and generic drugs. In principle, the goals of these studies are two-fold: (1) serve as bridging studies to provide supportive evidence for safety and efficacy of a drug product; and (2) ensure product quality and performance throughout the life time of a drug product in the presence of changes in formulation or manufacturing. Additionally, in the context of generic drugs, the current U.S. regulation dictates that evidence of bioequivalence and pharmaceutical equivalence provides the assurance of therapeutic equivalence, hence interchangeability. The conventional wisdom for bioequivalence studies indicates that the testing is best performed using the most accurate, sensitive, and reproducible approach available for the drug under examination. Accordingly, to date, comparative pharmacokinetic studies have been used in most cases for bioequivalence determination. In vitro tests are seldom utilized while pharmacodynamic studies and clinical trials are employed for locally acting drug products or when drug levels cannot be measured in the blood. This trend, however, is changing with the recent advances in pharmaceutical science and technology. For example, the introduction of the Biopharmaceutics Classification System (BCS) has provided a valuable tool for predicting drug absorption and bioavailability. The rapidly growing knowledge of pharmacogenetics/genomics combined with formulation science may facilitate a better understanding of the potential interplay between pharmaceutical characteristics and biological system in humans. In the future, an enhanced prediction and assessment of bioequivalence may be achieved through the rational design of formulations and use of in vitro, in situ or in silico test methods. Implicit in the inclusion of pharmaceutical equivalence as part of the definition of therapeutic equivalence has been the regulatory objective of achieving ’sameness’ to the greatest extent possible between a generic and innovator product, thereby avoiding unnecessary in vivo human testing. Perceivably, the better the drug substance and product are characterized, the more accurate and precise the determination of pharmaceutical equivalence will be. An increased assurance of pharmaceutical equivalence based on state-of-the-art science and technology may lessen the uncertainty of ’sameness’ in the clinical responses and reduce the burden for requiring in vivo evidence of bioequivalence. Over the last three decades, scientists have worked diligently to develop guidance and recommendations on how to demonstrate bioequivalence and pharmaceutical equivalence (hence therapeutic equivalence). Approaches to establishing any type of equivalence depend on the scientific knowledge and tools available at the time of evaluation. Continuing efforts and research are encouraged to improve the current approaches, and ensure product quality and performance over time for both new and generic drug products.
文摘Analysis of carcinogenicity data generally involves a trend test across all dose groups and a pairwise comparison of the high dose group with the control. The most commonly used test for a positive trend is the Cochran-Armitage test. This test is asymptotically normal. For the pairwise comparison of the high dose group with the control group, we propose two modifications: the first modification is to apply the test on the data from high dose and control groups after dropping the data from the low and the medium dose groups;the second modification is to adjust the test conditional on data from all dose groups. We compare the power performance of these two modifications for the pairwise comparisons.
文摘In an effort to promote the availability of safe and effective drugs, the US Food and Drug Administration is developing spectroscopic methods to assess the quality of drugs in the field. Here we report a rapid screening classification method for Tamiflu (oseltamivir phosphate) capsules using a portable Raman spectrometer to perform screening on three solid oral dosage strengths of Tamiflu, 30 mg, 45 mg and 75 mg. Tamiflu is an antiviral drug that is stockpiled for use in the event of pandemic influenza outbreak. The qualitative classification methods reported were developed using the Raman spectra of intact capsules. The classification algorithms used were able to reliably distinguish the three dosage strengths of Tamiflu. These qualitative models are validated with additional Tamiflu samples from different batches and simulated counterfeits of Tamiflu. The probability that a test sample belongs to each dosage strength class is calculated, and strict class predictions are used to assign each sample to a particular class. The classification methods reported here enable development of user-independent, field-deployable methods for finished drug products and are able to correctly assign 92% of the validation samples using authentic Tamiflu and 100% of the simulated counterfeits.
基金supported by National Science Foundation for Post-doctoral(2015M570231)Science and Technology Program of Tianjin(15PTCYSY00030)National Key research and development program(2016YFE0121400).
文摘Network toxicology combined with metabonomics is of great significance for the study of the toxic mechanism and prediction of toxicity of traditional Chinese medicines(TCMs).In this study,we reviewed the application of network toxicology based on LC-MS metabolomics,mainly in the study of toxic components and the toxicity mechanism of TCMs,which provides new ideas and methods for the further study of the toxicity mechanism of TCMs.
文摘Compared to small molecule process analytical technology (PAT) applications, biotechnology product PAT applications have certain unique challenges and opportunities. Understanding process dynamics of bioreactor cell culture process is essential to establish an appropriate process control strategy for biotechnology product PAT applications. Inline spectroscopic techniques for real time monitoring of bioreactor cell culture process have the distinct potential to develop PAT approaches in manufac- turing biotechnology drug products. However, the use of inline Fourier transform infrared (FTIR) spectroscopic techniques for bioreactor cell culture process monitoring has not been reported. In this work, real time inline FTIR Spectroscopy was applied to a lab scale bioreactor mAb IgG3 cell culture fluid biomolecular dynamic model. The technical feasibility of using FTIR Spectroscopy for real time tracking and monitoring four key cell culture metabolites (including glucose, glutamine, lactate, and ammonia) and protein yield at increasing levels of complexity (simple binary system, fully formulated media, actual bioreactor cell culture process) was evaluated via a stepwise approach. The FTIR fingerprints of the key metabolites were identified. The multivariate partial least squares (PLS) calibration models were established to correlate the process FTIR spectra with the concentrations of key metabolites and protein yield of in-process samples, either individually for each metabolite and protein or globally for all four metabolites simultaneously. Applying the 2'ld derivative pre-processing algorithm to the FTIR spectra helps to reduce the number of PLS latent variables needed significantly and thus simplify the interpretation of the PLS models. The validated PLS models show promise in predicting the concentration profiles of glucose, glutamine, lactate, and ammonia and protein yield over the course of the bioreactor cell culture process. Therefore, this work demonstrated the technical feasibility of real time monitoring of the bioreactor cell culture process via FTIR spectroscopy. Its implications for enabling cell culture PAT were discussed.
基金National Natural Science Foundation of China(81430096)China Drug Innovation Plan(2014ZX09507005,2014ZX09507005-003,2012ZX09304002,2012ZX09505001)
文摘Traditional Chinese medicine (TCM) has developed over thousands of years and has accumulated abundant clinical experience, forming a comprehensive and unique medical system. Emerging evidence has begun to illustrate TCM as an area of important medical rediscoveries. This review article briefly introduced the concept, significance, and technology of network pharmacology based on network biology and systems biology. It focused on the theoretical system and potential prospect of TCM network applied in TCM research and development including predicting new drug targets, action mechanism, new drug discovery; evaluating pharmacodynamics, pharmacokinetics, safety, toxicology, quality control, and bioinformatics of drugs. We also discussed the opportunities and challenges in the development and application of network pharmacology in the modernization of TCM research.
文摘Neonates are at increased risk of viral encephalopathies that can result in neurological dysfunction, seizures, permanent disability and even death. The neurological damage results from the combined effect of the virus and the immune response it elicits, thus finding tools to facilitate viral clearance from central nervous system (CNS) while minimizing neuron damage remains a critical challenge. Neonatal mice inoculated intraperitoneally with Tacaribe virus (TCRV) develop seizures, hindlimb paralysis and death within 15 days of inoculation. TCRV localizes to the CNS within days of challenge, primarily infecting astrocytes in the cerebellum and brain stem. We show that infection leads to inflammation, T cell and monocyte infiltration into the cerebellar parenchyma, apoptosis of astrocytes, neuronal degeneration and loss of Purkinje cells. Infiltrating antigen-specific T cells fail to clear the virus but drive the disease, as T-cell-deficient CD3ε KO mice survive TCRV infection with minimal inflammation or clinical manifestations despite no difference in CNS viral loads in comparison with T-cell sufficient mice. CD8+ T cells drive the pathology, which even in the absence of CD4+ T-cell help, infiltrate the parenchyma and mediate the apoptotic loss of cerebellar astrocytes, neurodegeneration and loss of Purkinje cells resulting in loss of balance, paralysis and death. CD4+ T cells are also pathogenic inducing gliosis and inflammation in the cerebellum and cerebrum that are associated with wasting and death several weeks after CD4+ T-cell transfer. These data demonstrate distinct pathogenic effects of CD4+ and CD8+ T cells and identify them as possible therapeutic targets.
文摘Posted on October 28,2016 by FDA Voice Here at FDA,we work diligently to be part of our nation’s solution to the opioid abuse epidemic.While there is no single solution to this complex problem,we continue to encourage efforts to develop new opioid formulations with abuse-deterrent properties that make it harder to abuse these powerful medications.