Pub Date : 2021-10-02DOI: 10.30895/1991-2919-2021-11-2-185-192
A. Alekseeva, M. V. Gavrilin, T. B. Shemeryankina, M. S. Smirnova, E. P. Fedorova, T. Kargina, O. Novikov, S. Kovaleva, N. Boyko
A great variety of components in multivitamin preparations containing folic acid, and a variety of test methods and conditions of folic acid determination proposed by manufacturers, require alignment of test procedures for products with similar composition.The aim of the study was to compare the results of experimental verification of folic acid determination procedures which use reversed phase high-performance liquid chromatography (RP HPLC) with isocratic elution mode. Materials and methods: The Agilent 1260 Infinity II LC system with a diode array detector (280 nm), isocratic elution mode, C8- and C18-bonded silica gel chromatographic columns, model mixtures containing folic acid, cyanocobalamin, ferrous sulfate, and potassium iodide, were used in the study.Results: The lowest relative standard deviation of the folic acid peak area (RSD=0.09%), and the lowest asymmetry factor (As=1.04) for folic acid were observed for the model mixture “ferrous sulfate+folic acid+cyanocobalamin” and the following test conditions. Column: 250×4.0 mm, silica gel for chromatography, octylsilyl (C8), endcapped; mobile phase: methanol‒phosphate buffer (12:88), pH 6.6; column temperature: 25ºС. The study demonstrated the feasibility of using these conditions for determination of pteroic acid impurity with simultaneous precipitation of interfering ferrous ions, using ethylenediaminetetraacetic acid solution, pH 9.5, as a solvent.Conclusions: RP HPLC can be recommended as an optimal aligned test procedure for determination of folic acid in combination products. It is recommended to use a solution containing folic and pteroic acids for system suitability testing.
{"title":"Determination of Folic Acid in Multivitamin Preparations by Reversed Phase HPLC","authors":"A. Alekseeva, M. V. Gavrilin, T. B. Shemeryankina, M. S. Smirnova, E. P. Fedorova, T. Kargina, O. Novikov, S. Kovaleva, N. Boyko","doi":"10.30895/1991-2919-2021-11-2-185-192","DOIUrl":"https://doi.org/10.30895/1991-2919-2021-11-2-185-192","url":null,"abstract":"A great variety of components in multivitamin preparations containing folic acid, and a variety of test methods and conditions of folic acid determination proposed by manufacturers, require alignment of test procedures for products with similar composition.The aim of the study was to compare the results of experimental verification of folic acid determination procedures which use reversed phase high-performance liquid chromatography (RP HPLC) with isocratic elution mode. Materials and methods: The Agilent 1260 Infinity II LC system with a diode array detector (280 nm), isocratic elution mode, C8- and C18-bonded silica gel chromatographic columns, model mixtures containing folic acid, cyanocobalamin, ferrous sulfate, and potassium iodide, were used in the study.Results: The lowest relative standard deviation of the folic acid peak area (RSD=0.09%), and the lowest asymmetry factor (As=1.04) for folic acid were observed for the model mixture “ferrous sulfate+folic acid+cyanocobalamin” and the following test conditions. Column: 250×4.0 mm, silica gel for chromatography, octylsilyl (C8), endcapped; mobile phase: methanol‒phosphate buffer (12:88), pH 6.6; column temperature: 25ºС. The study demonstrated the feasibility of using these conditions for determination of pteroic acid impurity with simultaneous precipitation of interfering ferrous ions, using ethylenediaminetetraacetic acid solution, pH 9.5, as a solvent.Conclusions: RP HPLC can be recommended as an optimal aligned test procedure for determination of folic acid in combination products. It is recommended to use a solution containing folic and pteroic acids for system suitability testing.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":"55 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89352517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-10-02DOI: 10.30895/1991-2919-2021-11-2-167-173
M. Komarova
Until now, there have been no effective treatments for some ophthalmic diseases that have high social significance. Development of therapeutic approaches to such diseases may be complicated due to challenges in diagnosis and selection of clinical trial endpoints. The aim of the study was to analyse current approaches to selection of endpoints in clinical trials of ophthalmic drugs. Clinical efficacy studies of new medicinal products use surrogate endpoints in addition to clinical endpoints. However, currently used surrogate endpoints are not always relevant and do not fully reflect changes in the status of patients with chronic or progressive diseases. The study analysed published approaches to the selection of endpoints in clinical studies of ophthalmic drugs intended for the treatment of glaucoma, uveitis, dry eye syndrome, and age-related macular degeneration. It was demonstrated that the choice of surrogate endpoints in a clinical trial should take into account specific aspects of a particular disease. The assessment of dynamic patterns of changes in visual functions generally requires a complex approach for a comprehensive characterisation of the eye condition in a particular disease. The paper analyses the possibility of using potential surrogate endpoints in studies of the most common eye diseases, and highlights that none of them has been recommended for use in clinical trials or routine clinical practice.
{"title":"Selection of Endpoints for Clinical Studies of Ophthalmic Drugs","authors":"M. Komarova","doi":"10.30895/1991-2919-2021-11-2-167-173","DOIUrl":"https://doi.org/10.30895/1991-2919-2021-11-2-167-173","url":null,"abstract":"Until now, there have been no effective treatments for some ophthalmic diseases that have high social significance. Development of therapeutic approaches to such diseases may be complicated due to challenges in diagnosis and selection of clinical trial endpoints. The aim of the study was to analyse current approaches to selection of endpoints in clinical trials of ophthalmic drugs. Clinical efficacy studies of new medicinal products use surrogate endpoints in addition to clinical endpoints. However, currently used surrogate endpoints are not always relevant and do not fully reflect changes in the status of patients with chronic or progressive diseases. The study analysed published approaches to the selection of endpoints in clinical studies of ophthalmic drugs intended for the treatment of glaucoma, uveitis, dry eye syndrome, and age-related macular degeneration. It was demonstrated that the choice of surrogate endpoints in a clinical trial should take into account specific aspects of a particular disease. The assessment of dynamic patterns of changes in visual functions generally requires a complex approach for a comprehensive characterisation of the eye condition in a particular disease. The paper analyses the possibility of using potential surrogate endpoints in studies of the most common eye diseases, and highlights that none of them has been recommended for use in clinical trials or routine clinical practice.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":"60 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89176350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-09-22DOI: 10.30895/1991-2919-2021-11-4-255-262
O. Klementyeva, A. Lunev, C. A. Lunyova
Radiopharmaceuticals differ from other medicines mainly by the specific nature of their pharmacological action based on radioactivity, by absence of multiple-dose regimens, and by miniscule concentrations of the active pharmaceutical ingredient (10-9–10-12 mol/L). However, the official regulations and standards do not contain specific requirements for preclinical evaluation of radiopharmaceuticals. The aim of the study was to summarise preclinical data on general toxicity of therapeutic radiopharmaceuticals, which were obtained by the Laboratory of Preclinical and Clinical Studies of Radiopharmaceuticals of the Federal State Budgetary Institution ‘State Research Center of the Russian Federation¾Burnasyan Federal Medical Biophysical Center’ of the Federal Medical Biological Agency. Results: the authors analysed criteria for: selection of the study design based on physico-chemical nature of the active pharmaceutical ingredient; calculation of doses and selection of dosage regimens for radiopharmaceuticals with different administration routes; radiation safety for personnel performing the study. The authors used the data on three therapeutic radiopharmaceuticals to formulate methodological approaches to preclinical evaluation of their general toxic properties. The analysis of long-term experience in preclinical studies of therapeutic radiopharmaceuticals demonstrated the need for a judicious individual approach to the development of a preclinical study design. The authors proposed methodological approaches to preclinical evaluation of general toxic properties of therapeutic radiopharmaceuticals, which make it possible to adequately assess potential toxic effects and obtain meaningful study results. Conclusions: there is a need for a specific guideline for preclinical studies of therapeutic radiopharmaceuticals, which would take into account specific pharmacological action and nuclear-physical characteristics of radionuclides.
{"title":"Methodological Approaches to Preclinical Evaluation of General Toxicity of Therapeutic Radiopharmaceuticals","authors":"O. Klementyeva, A. Lunev, C. A. Lunyova","doi":"10.30895/1991-2919-2021-11-4-255-262","DOIUrl":"https://doi.org/10.30895/1991-2919-2021-11-4-255-262","url":null,"abstract":"Radiopharmaceuticals differ from other medicines mainly by the specific nature of their pharmacological action based on radioactivity, by absence of multiple-dose regimens, and by miniscule concentrations of the active pharmaceutical ingredient (10-9–10-12 mol/L). However, the official regulations and standards do not contain specific requirements for preclinical evaluation of radiopharmaceuticals. The aim of the study was to summarise preclinical data on general toxicity of therapeutic radiopharmaceuticals, which were obtained by the Laboratory of Preclinical and Clinical Studies of Radiopharmaceuticals of the Federal State Budgetary Institution ‘State Research Center of the Russian Federation¾Burnasyan Federal Medical Biophysical Center’ of the Federal Medical Biological Agency. Results: the authors analysed criteria for: selection of the study design based on physico-chemical nature of the active pharmaceutical ingredient; calculation of doses and selection of dosage regimens for radiopharmaceuticals with different administration routes; radiation safety for personnel performing the study. The authors used the data on three therapeutic radiopharmaceuticals to formulate methodological approaches to preclinical evaluation of their general toxic properties. The analysis of long-term experience in preclinical studies of therapeutic radiopharmaceuticals demonstrated the need for a judicious individual approach to the development of a preclinical study design. The authors proposed methodological approaches to preclinical evaluation of general toxic properties of therapeutic radiopharmaceuticals, which make it possible to adequately assess potential toxic effects and obtain meaningful study results. Conclusions: there is a need for a specific guideline for preclinical studies of therapeutic radiopharmaceuticals, which would take into account specific pharmacological action and nuclear-physical characteristics of radionuclides.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":"45 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86357807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-03DOI: 10.30895/1991-2919-2021-11-2-130-134
S. Kuleshova, S. A. Protsak, S. A. Lisunova, G. Y. Romanyuk
The culture media quality, which depends to a large extent on growth promotion properties, determines the reliability and accuracy of test results obtained by microbiological methods. The procedure for culture media preparation is quite labourconsuming and includes several stages: successive dissolution of components exactly as specified in the recipe (qualitative and quantitative composition), sterilisation, adjusting the pH of the medium, and testing of growth promotion properties—therefore it is important to demonstrate the stability of each particular culture medium.The aim of the study was to evaluate growth promotion properties of the culture media prepared in the laboratory from a dry mixture, and to assess their stability during long-term storage.Materials and methods: stability testing was performed for fluid thioglycollate medium (FTM) and soybean-casein digest broth (SCD) prepared in the laboratory. FTM growth promotion properties were tested using the following test microorganisms: Bacillus subtilis ATCC 6633, Clostridium sporogenes ATCC 19404, Pseudomonas aeruginosa ATCC 9027, Staphylococcus aureus ATCC 6538. SCD growth promotion properties were tested using: Aspergillus brasiliensis ATCC 16404, Candida albicans ATCC 10231, Bacillus subtilis ATCC 6633. The stability study was carried out for 6 months, assessing changes in appearance and growth promotion properties. The test media were stored at room temperature and in a refrigerator at 2–8 °C.Results: no growth of the anaerobic microorganism Clostridium sporogenes was observed in FTM after 3 months, regardless of storage conditions. Later on, there was no growth of the gram-positive microorganisms Bacillus subtilis and Staphylococcus aureus, which are more sensitive to the storage conditions than Pseudomonas aeruginosa. The growth promotion properties of the SCD prepared in the laboratory did not change during 6 months of storage.Conclusions: FTM prepared from a dry mixture remains stable and retains its growth promotion properties for no more than two months when stored in a refrigerator at 2–8 °C. SCD can remain stable for 6 months, both at room temperature and when stored in the refrigerator.
{"title":"Stability of Ready-to-Use and Laboratory-Prepared Culture Media","authors":"S. Kuleshova, S. A. Protsak, S. A. Lisunova, G. Y. Romanyuk","doi":"10.30895/1991-2919-2021-11-2-130-134","DOIUrl":"https://doi.org/10.30895/1991-2919-2021-11-2-130-134","url":null,"abstract":"The culture media quality, which depends to a large extent on growth promotion properties, determines the reliability and accuracy of test results obtained by microbiological methods. The procedure for culture media preparation is quite labourconsuming and includes several stages: successive dissolution of components exactly as specified in the recipe (qualitative and quantitative composition), sterilisation, adjusting the pH of the medium, and testing of growth promotion properties—therefore it is important to demonstrate the stability of each particular culture medium.The aim of the study was to evaluate growth promotion properties of the culture media prepared in the laboratory from a dry mixture, and to assess their stability during long-term storage.Materials and methods: stability testing was performed for fluid thioglycollate medium (FTM) and soybean-casein digest broth (SCD) prepared in the laboratory. FTM growth promotion properties were tested using the following test microorganisms: Bacillus subtilis ATCC 6633, Clostridium sporogenes ATCC 19404, Pseudomonas aeruginosa ATCC 9027, Staphylococcus aureus ATCC 6538. SCD growth promotion properties were tested using: Aspergillus brasiliensis ATCC 16404, Candida albicans ATCC 10231, Bacillus subtilis ATCC 6633. The stability study was carried out for 6 months, assessing changes in appearance and growth promotion properties. The test media were stored at room temperature and in a refrigerator at 2–8 °C.Results: no growth of the anaerobic microorganism Clostridium sporogenes was observed in FTM after 3 months, regardless of storage conditions. Later on, there was no growth of the gram-positive microorganisms Bacillus subtilis and Staphylococcus aureus, which are more sensitive to the storage conditions than Pseudomonas aeruginosa. The growth promotion properties of the SCD prepared in the laboratory did not change during 6 months of storage.Conclusions: FTM prepared from a dry mixture remains stable and retains its growth promotion properties for no more than two months when stored in a refrigerator at 2–8 °C. SCD can remain stable for 6 months, both at room temperature and when stored in the refrigerator.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74622254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-03DOI: 10.30895/1991-2919-2021-11-2-115-120
N. P. Neugodova, O. Shapovalova, G. A. Sapozhnikova, E. O. Stepanyuk
The State Pharmacopoeia of the Russian Federation, 14th edition states that implants are a sterile dosage form, and have to be tested for pyrogens. However, it does not provide details on how the test should be performed for this dosage form.The aim of the study was to develop a LAL test procedure for detection of bacterial endotoxins (BE) in implants, using the example of a goserelin product.Materials and methods: BE extraction from the implant surface into an aqueous medium was performed with subsequent BE detection in the extract by turbidimetric kinetic test. The implant was then dissolved in dimethyl sulfoxide, and the obtained goserelin solution was tested for BEs using the gel-clot test.Results: the analysis of the Russian and foreign pharmacopoeial approaches to pyrogenic substance detection in hormonal implants helped to develop two sample preparation procedures for determination of BE content (in the extract and the implant solution). It was demonstrated that the BE content in the water extract did not exceed 0.01 EU/mL and was less than 0.07 EU per implant. The BE content in the implant solution was less than 8.3 EU per 1 mg of goserelin, which is almost eleven-fold lower than the theoretically-derived limit.Conclusions: the authors developed two test procedures for BE detection in hormonal implants using the LAL test, which could be included in manufacturers’ product files. The first procedure involves testing of the water extract from the implant surface and establishes the BE limit of no more than 20 EU/product. The second procedure involves complete dissolution of the implant in dimethyl sulfoxide and establishes the limit of not more than 97.22 EU per 1 mg of goserelin.
{"title":"Detection of Pyrogens in Hormonal Implants Using the LAL Test","authors":"N. P. Neugodova, O. Shapovalova, G. A. Sapozhnikova, E. O. Stepanyuk","doi":"10.30895/1991-2919-2021-11-2-115-120","DOIUrl":"https://doi.org/10.30895/1991-2919-2021-11-2-115-120","url":null,"abstract":"The State Pharmacopoeia of the Russian Federation, 14th edition states that implants are a sterile dosage form, and have to be tested for pyrogens. However, it does not provide details on how the test should be performed for this dosage form.The aim of the study was to develop a LAL test procedure for detection of bacterial endotoxins (BE) in implants, using the example of a goserelin product.Materials and methods: BE extraction from the implant surface into an aqueous medium was performed with subsequent BE detection in the extract by turbidimetric kinetic test. The implant was then dissolved in dimethyl sulfoxide, and the obtained goserelin solution was tested for BEs using the gel-clot test.Results: the analysis of the Russian and foreign pharmacopoeial approaches to pyrogenic substance detection in hormonal implants helped to develop two sample preparation procedures for determination of BE content (in the extract and the implant solution). It was demonstrated that the BE content in the water extract did not exceed 0.01 EU/mL and was less than 0.07 EU per implant. The BE content in the implant solution was less than 8.3 EU per 1 mg of goserelin, which is almost eleven-fold lower than the theoretically-derived limit.Conclusions: the authors developed two test procedures for BE detection in hormonal implants using the LAL test, which could be included in manufacturers’ product files. The first procedure involves testing of the water extract from the implant surface and establishes the BE limit of no more than 20 EU/product. The second procedure involves complete dissolution of the implant in dimethyl sulfoxide and establishes the limit of not more than 97.22 EU per 1 mg of goserelin.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85300575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-03DOI: 10.30895/1991-2919-2021-11-2-81-93
O. Basova, I. V. Lysikova, O. Ivanova
Patient subgroup analysis plays an important role in interpretation of confirmatory clinical trial results and is mandatory in most cases. The purpose of subgroup analysis is to assess the consistency (heterogeneity) of the treatment effect in subgroups of patients identified based on such characteristics as demographics, stage and severity of the underlying disease, presence of a certain genetic mutation, etc. However, existing methodological issues (the problem of multiple comparisons, detection of differences between subgroups by chance alone, etc.) make it difficult to carry out the analysis and often lead to controversial conclusions. The aim of the study was to analyse and summarise foreign regulatory approaches to subgroup analysis in confirmatory clinical trials, and to elaborate science-based requirements for subgroup analysis and interpretation of the results by clinical trial sponsors and experts when assessing the risk-benefit ratio of medicinal products for the purpose of their authorisation in Russia and the Eura sian Economic Union. This paper discusses the objectives of subgroup analysis and statistical approaches to its performance, provides relevant examples of such analysis from regulatory practice. It describes approaches to interpretation of subgroup analysis depending on the presence/absence of evidence supporting the primary hypothesis of the study, the nature of the experimental medicinal product’s heterogeneous effects in the subgroups, and selection of the subgroups. The paper highlights areas of concern in subgroup analysis, potential controversies in interpretation of the obtained results, and regulatory expectations. The recommendations presented in the paper can be used by experts in the assessment of the risk-benefit ratio, as well as by medicine developers in the preparation of clinical trial protocols and reports.
{"title":"Specific Aspects and Significance of Subgroup Assessment in Confirmatory Clinical Trials","authors":"O. Basova, I. V. Lysikova, O. Ivanova","doi":"10.30895/1991-2919-2021-11-2-81-93","DOIUrl":"https://doi.org/10.30895/1991-2919-2021-11-2-81-93","url":null,"abstract":"Patient subgroup analysis plays an important role in interpretation of confirmatory clinical trial results and is mandatory in most cases. The purpose of subgroup analysis is to assess the consistency (heterogeneity) of the treatment effect in subgroups of patients identified based on such characteristics as demographics, stage and severity of the underlying disease, presence of a certain genetic mutation, etc. However, existing methodological issues (the problem of multiple comparisons, detection of differences between subgroups by chance alone, etc.) make it difficult to carry out the analysis and often lead to controversial conclusions. The aim of the study was to analyse and summarise foreign regulatory approaches to subgroup analysis in confirmatory clinical trials, and to elaborate science-based requirements for subgroup analysis and interpretation of the results by clinical trial sponsors and experts when assessing the risk-benefit ratio of medicinal products for the purpose of their authorisation in Russia and the Eura sian Economic Union. This paper discusses the objectives of subgroup analysis and statistical approaches to its performance, provides relevant examples of such analysis from regulatory practice. It describes approaches to interpretation of subgroup analysis depending on the presence/absence of evidence supporting the primary hypothesis of the study, the nature of the experimental medicinal product’s heterogeneous effects in the subgroups, and selection of the subgroups. The paper highlights areas of concern in subgroup analysis, potential controversies in interpretation of the obtained results, and regulatory expectations. The recommendations presented in the paper can be used by experts in the assessment of the risk-benefit ratio, as well as by medicine developers in the preparation of clinical trial protocols and reports.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":"93 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75435187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-03DOI: 10.30895/1991-2919-2021-11-2-121-129
N. Antonova, S. S. Prokhvatilova, E. Shefer, A. Kalinin, I. M. Morgunov, T. A. Golomazova, U. S. Legon’kova
Arbutin is the main active ingredient in many herbal medicinal products that have diuretic, antimicrobial, bactericidal, and antioxidant effects. Many of these products are mixtures of different herbal substances. Therefore, the approaches to quality control of HMPs can vary significantly. The aim of the study was to compare arbutin assay procedures used in quality control of arbutin-containing products. Materials and methods. Samples of the following HMPs were used in the study: monocomponent Bearberry Leaf and multicomponent Brusniver® (herbal mixture, powder). The test methods used were titrimetry, ultraviolet-visible spectrophotometry, and high-performance liquid chromatography (HPLC). Results. The authors compared five arbutin assay procedures described in the monographs and product files for arbutin-containing HMPs. Conclusions. It has been established that the analysed procedures cannot be used interchangeably as equivalent test methods; the limits for arbutin have to be established for each specific procedure. Iodometric titration is the most labour- and time-consuming method, and the determined titration endpoint is a subjective assessment. Spectrophotometric methods do not require the use of an arbutin reference standard, but they can give overestimated results as compared to the HPLC and titrimetry methods. HPLC methods are more selective, but they require the use of reference standards. The recommended test methods for HMP quality control are HPLC and visible spectrophotometry; the titrimetric method is recommended for replacement.
{"title":"Determination of Arbutin in Herbal Medicinal Products","authors":"N. Antonova, S. S. Prokhvatilova, E. Shefer, A. Kalinin, I. M. Morgunov, T. A. Golomazova, U. S. Legon’kova","doi":"10.30895/1991-2919-2021-11-2-121-129","DOIUrl":"https://doi.org/10.30895/1991-2919-2021-11-2-121-129","url":null,"abstract":"Arbutin is the main active ingredient in many herbal medicinal products that have diuretic, antimicrobial, bactericidal, and antioxidant effects. Many of these products are mixtures of different herbal substances. Therefore, the approaches to quality control of HMPs can vary significantly. The aim of the study was to compare arbutin assay procedures used in quality control of arbutin-containing products. Materials and methods. Samples of the following HMPs were used in the study: monocomponent Bearberry Leaf and multicomponent Brusniver® (herbal mixture, powder). The test methods used were titrimetry, ultraviolet-visible spectrophotometry, and high-performance liquid chromatography (HPLC). Results. The authors compared five arbutin assay procedures described in the monographs and product files for arbutin-containing HMPs. Conclusions. It has been established that the analysed procedures cannot be used interchangeably as equivalent test methods; the limits for arbutin have to be established for each specific procedure. Iodometric titration is the most labour- and time-consuming method, and the determined titration endpoint is a subjective assessment. Spectrophotometric methods do not require the use of an arbutin reference standard, but they can give overestimated results as compared to the HPLC and titrimetry methods. HPLC methods are more selective, but they require the use of reference standards. The recommended test methods for HMP quality control are HPLC and visible spectrophotometry; the titrimetric method is recommended for replacement.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":"199 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74470492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-03DOI: 10.30895/1991-2919-2021-11-2-135-142
P. V. Shadrin, T. A. Batuashvili, L. V. Simutenko, N. P. Neugodova
The median lethal dose (LD50) and low lethal dose (LD10) are calculated in acute toxicity studies, as well as during specific activity assessment of some medicines. The aim of the study was to develop a procedure for using CombiStats to calculate LD50 and LD10. The authors proposed a step-by-step algorithm for processing bioassay results using the CombiStats biometric software (median effective dose determination model, probit analysis) with conversion of doses to simple fractions (fractions of the maximum dose) to calculate LD50 and LD10. They compared LD50 and LD10 calculation results obtained using CombiStats with those obtained using electronic spreadsheets according to the Bliss–Miller–Tainter–Prozorovsky method described in the State Pharmacopoeia of the Russian Federation (General Monograph 1.1.0014.15). It has been demonstrated that the use of CombiStats sometimes has advantages over the use of the pharmacoepoeial method.
{"title":"Calculation of the Median Lethal Dose and Low Lethal Dose Using the CombiStats Biometric Software","authors":"P. V. Shadrin, T. A. Batuashvili, L. V. Simutenko, N. P. Neugodova","doi":"10.30895/1991-2919-2021-11-2-135-142","DOIUrl":"https://doi.org/10.30895/1991-2919-2021-11-2-135-142","url":null,"abstract":"The median lethal dose (LD50) and low lethal dose (LD10) are calculated in acute toxicity studies, as well as during specific activity assessment of some medicines. The aim of the study was to develop a procedure for using CombiStats to calculate LD50 and LD10. The authors proposed a step-by-step algorithm for processing bioassay results using the CombiStats biometric software (median effective dose determination model, probit analysis) with conversion of doses to simple fractions (fractions of the maximum dose) to calculate LD50 and LD10. They compared LD50 and LD10 calculation results obtained using CombiStats with those obtained using electronic spreadsheets according to the Bliss–Miller–Tainter–Prozorovsky method described in the State Pharmacopoeia of the Russian Federation (General Monograph 1.1.0014.15). It has been demonstrated that the use of CombiStats sometimes has advantages over the use of the pharmacoepoeial method.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":"719 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76914127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-03DOI: 10.30895/1991-2919-2021-11-2-94-103
I. A. Proskurina, E. A. Petraneva, D. Goryachev
Diabetes is a serious public health problem and one of the major chronic noncommunicable diseases. A lengthy stepwise treatment, and the need for an individualised approach to antidiabetic therapy, pose serious challenges for medicine developers. For all new hypoglycaemic medicines, there has been a centralised authorisation procedure in the European Union (EU) since 2005, which ensures a unified approach to efficacy and safety assessment. The aim of the study was to analyse current requirements for planning clinical trials of hypoglycaemic medicines containing new active substances (except for insulin products). The recommendations for diagnosis and treatment of type 2 diabetes, prepared by the European Association for the Study of Diabetes (EASD) and the American Diabetes Association (ADA) in 2019, suggest a step-by-step approach to intensification of treatment to maintain glycaemic targets, which takes account of concomitant cardiovascular or other diseases, and clinical characteristics of patients. The analysis of EASD/ADA documents and scientific literature helped to develop recommendations on the basic principles of planning and conducting clinical trials at the final stages of hypoglycaemic medicine development. The paper describes new approaches to clinical trials, which allow for a more reliable assessment of the treatment effectiveness. The strategy for the assessment of therapeutic effect should be carefully planned, justified, and reflected in variables of interest, clinical trial design, and statistical analysis of the trial results. The main efficacy criterion in confirmatory clinical trials of hypoglycaemic medicines should be the demonstration of benefits in improving glycaemic control. The medicine’s effect on the body weight may be considered as a secondary endpoint. An essential requirement is confirmation of the medicines’ cardiovascular safety, while potential additional benefits are reduction or prevention of risks of cardiovascular disease development. The clinical trial protocol should provide definitions for intercurrent events and hypoglycaemia. A comprehensive safety study of a new hypoglycaemic medicine should involve identification of anticipated or known side effects characteristic of a particular pharmacological class. The provided recommendations may be helpful for medicine developers, and for experts who perform assessment of clinical trial programmes and regulatory submissions for hypoglycaemic medicines.
{"title":"Recommendations on the Clinical Trial Programme for Diabetes Medicines","authors":"I. A. Proskurina, E. A. Petraneva, D. Goryachev","doi":"10.30895/1991-2919-2021-11-2-94-103","DOIUrl":"https://doi.org/10.30895/1991-2919-2021-11-2-94-103","url":null,"abstract":"Diabetes is a serious public health problem and one of the major chronic noncommunicable diseases. A lengthy stepwise treatment, and the need for an individualised approach to antidiabetic therapy, pose serious challenges for medicine developers. For all new hypoglycaemic medicines, there has been a centralised authorisation procedure in the European Union (EU) since 2005, which ensures a unified approach to efficacy and safety assessment. The aim of the study was to analyse current requirements for planning clinical trials of hypoglycaemic medicines containing new active substances (except for insulin products). The recommendations for diagnosis and treatment of type 2 diabetes, prepared by the European Association for the Study of Diabetes (EASD) and the American Diabetes Association (ADA) in 2019, suggest a step-by-step approach to intensification of treatment to maintain glycaemic targets, which takes account of concomitant cardiovascular or other diseases, and clinical characteristics of patients. The analysis of EASD/ADA documents and scientific literature helped to develop recommendations on the basic principles of planning and conducting clinical trials at the final stages of hypoglycaemic medicine development. The paper describes new approaches to clinical trials, which allow for a more reliable assessment of the treatment effectiveness. The strategy for the assessment of therapeutic effect should be carefully planned, justified, and reflected in variables of interest, clinical trial design, and statistical analysis of the trial results. The main efficacy criterion in confirmatory clinical trials of hypoglycaemic medicines should be the demonstration of benefits in improving glycaemic control. The medicine’s effect on the body weight may be considered as a secondary endpoint. An essential requirement is confirmation of the medicines’ cardiovascular safety, while potential additional benefits are reduction or prevention of risks of cardiovascular disease development. The clinical trial protocol should provide definitions for intercurrent events and hypoglycaemia. A comprehensive safety study of a new hypoglycaemic medicine should involve identification of anticipated or known side effects characteristic of a particular pharmacological class. The provided recommendations may be helpful for medicine developers, and for experts who perform assessment of clinical trial programmes and regulatory submissions for hypoglycaemic medicines. ","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":"71 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77261586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-04-30DOI: 10.30895/1991-2919-2021-11-2-104-114
O. Evdokimova, A. Beketova, M. N. Lyakina
The relevance of this study stems from the need for alignment of test methods used for identification and assay of anthracene derivatives in herbal preparations and herbal medicinal products. The aim of the study was to analyse Russian and international quality standards and to identify the most specific and sensitive test methods that could be used for herbal medicines containing anthracene derivatives. The comparative analysis of requirements in the Identification, Determination of major classes of bioactive compounds, and Assay parts of the Russian and foreign pharmacopoeial monographs for herbal preparations and herbal medicinal products containing anthracene derivatives, demonstrated that the main test method used for identification is thin layer chromatography, while assays most often rely on spectrophotometry. The so-called “consistent standardisation” principle is implemented in the Russian quality standards as regards alignment of methods used for anthracene derivative determination in herbal preparations (i.e. active pharmaceutical ingredients, APIs) and herbal medicinal products containing these APIs. The comparative analysis of requirements in the Russian and foreign quality standards for herbal medicines containing anthracene derivatives demonstrated the need for elaboration of two general chapters: Qualitative analysis of anthracene derivatives in herbal medicines and Quantitative analysis of anthracene derivatives in herbal medicines.
{"title":"Determination of Anthracene Derivatives in Herbal Medicines","authors":"O. Evdokimova, A. Beketova, M. N. Lyakina","doi":"10.30895/1991-2919-2021-11-2-104-114","DOIUrl":"https://doi.org/10.30895/1991-2919-2021-11-2-104-114","url":null,"abstract":"The relevance of this study stems from the need for alignment of test methods used for identification and assay of anthracene derivatives in herbal preparations and herbal medicinal products. The aim of the study was to analyse Russian and international quality standards and to identify the most specific and sensitive test methods that could be used for herbal medicines containing anthracene derivatives. The comparative analysis of requirements in the Identification, Determination of major classes of bioactive compounds, and Assay parts of the Russian and foreign pharmacopoeial monographs for herbal preparations and herbal medicinal products containing anthracene derivatives, demonstrated that the main test method used for identification is thin layer chromatography, while assays most often rely on spectrophotometry. The so-called “consistent standardisation” principle is implemented in the Russian quality standards as regards alignment of methods used for anthracene derivative determination in herbal preparations (i.e. active pharmaceutical ingredients, APIs) and herbal medicinal products containing these APIs. The comparative analysis of requirements in the Russian and foreign quality standards for herbal medicines containing anthracene derivatives demonstrated the need for elaboration of two general chapters: Qualitative analysis of anthracene derivatives in herbal medicines and Quantitative analysis of anthracene derivatives in herbal medicines.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":"289 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77048805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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