BCS-based biowaiver using biphasic dissolution test
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PURPOSE Biowaivers based on BCS class can be used to establish therapeutic equivalence based on dissolution tests. The objective of the present study was to compare a biphasic dissolution system with compendial methods in examining the in vitro performance of metronidazole drug products. We hypothesized that where in vitro equivalence was not achieved in compendial methods, the partitioning profile to the organic phase in the biphasic system could signal bioequivalence among the drug products and comparator pharmaceutical product (CPP). CONCLUSIONS RESULTS None of the tested metronidazole products were in vitro equivalent to the CPP or to other manufacturers in compendial buffer. The tested metronidazole products followed a similar pattern than that obtained in the compendial buffer in the aqueous phase of the biphasic system. METHODS The in vitro performance of metronidazole drug products marketed in different countries of the Americas was compared to the US comparator pharmaceutical product (CPP) to determine if they met in vitro bioequivalence criteria. Disintegration test The test was performed according to USP general chapter <701>. Disintegration time was measured in a disintegration tester (Eureka, Germany) using 900 mL of phosphate buffer pH 6.8 at 37 ± 2 °C as medium. Six tablets of each drug product were tested. Dissolution test Five commercial metronidazole tablets were tested in compendial Simulated Intestinal Fluid (SIF), as well as in physiological buffer capacity (5mM phosphate buffer at pH 6.8, 900 mL). The tablets were also tested in a biphasic dissolution system in which the aqueous layer was composed of 200 mL of 5 mM phosphate buffer (pH 6.8) with 100 mL of n-octanol on top. REFERENCES AND ACKNOWLEDGEMENTS Amaral Silva, D.; Al-Gousous, J.; Davies, N. M.; Bou Chacra, N.; Webster, G. K.; Lipka, E.; Amidon, G. L.; Löbenberg, R. Biphasic Dissolution as an Exploratory Method during Early Drug Product Development. Pharmaceutics 2020, 12 (5), 420. https://doi.org/10.3390/pharmaceutics12050420. Mudie, D. M.; Shi, Y.; Ping, H.; Gao, P.; Amidon, G. L.; Amidon, G. E. Mechanistic Analysis of Solute Transport in an in Vitro Physiological Two-Phase Dissolution Apparatus. Biopharm. Drug Dispos. 2012, 33, 378–402. https://doi.org/10.1002/bdd.1803. Daniela Amara Silva is supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Breast Cancer Research program, under Award No. W81XWH-17-1-0470. Opinions, interpretations, conclusions and recommendations are those of the author and not necessarily endorsed by the Department of Defense • None of the tested metronidazole products demonstrated in vitro equivalence to the CPP in the monophasic dissolution methods, i.e. SIF and physiological buffer capacity. • The monophasic aqueous systems seem to be overdiscriminating. • The correlation of the organic phase of the biphasic system showed a similar partitioning pattern for all the generic drug products and CPP, which could indicate in vitro equivalence. • The application of biphasic dissolution to highly soluble drug and formulations has beneficial attributes to estimate the in vivo behavior and performance. • Further in vitro studies with other products are needed to confirm and refine these findings. % Dissolved Time BCS - based biowaiver using biphasic dissolution test Daniela Amaral Silva 1 , Katherine Curo Melo 1,2 , Neal M. Davies 1 , Nadia Bou - Chacra 2 , Humberto G. Ferraz 2 , Raimar Löbenberg 1 . 1 Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada. 2 Faculty of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508 - 000, Brazil. Interchangeable/bioequivalent? Surrogate test PRODUCT DISINTEGRATION Time (min) SD FLAGYL-USP (CPP) 5.32 0.43 FLAGYL-MEXICO 18.27 0.58 FLAGENASE 10.16 0.07 COLPOFILIN 0.60 0.22 METRAL 13.32 0.78 0 20 40 60 80 100 0 10 20 30 40 50 60 % Dissolved Time (min) 0 20 40 60 80 0 10 20 30 40 50 60 Time( min) Plasma concentration Time Table 1. Disintegration time of different commercially available metronidazole IR tablets Figure 1. Dissolution profiles of metronidazole formulations in SIF (solid lines) and low buffer capacity phosphate buffer (5mM – dashed lines). Figure 2. Biphasic dissolution profiles of metronidazole formulations in the aqueous (dashed lines) and organic phases (solid lines). Flagyl-USP, Flagyl-Mex, Flagenase, Colpofilin, Metral 0 5 10 15 20 25 30 0 2 4 6 8 10 12 % partitioned generic product % partitioned CPP This was not the case for the organic phase partition profiles. All the tested products had a good correlation to the CPP, which could indicate in vitro equivalence between these products. This could potentially allow for a biowaiver application. Figure 3. Correlation between the comparator pharmaceutical product (CPP) and generic products of the amount partitioned to the organic phase. Only data after full tablet disintegration were used. Flagyl-Mex, Flagenase, Colpofilin, Metral FLAGYL-USP (CPP) FLAGYL-MEXICO 0.996 FLAGENASE 0.95 COLPOFILIN 0.95 METRAL 0.97 Table 2. Correlation coefficient (R 2 ) between the CPP and generic products Intestinal lumen Blood stream Epithelial cells Stomach residence time for half emptying à up to 17 minutes
Transcript of BCS-based biowaiver using biphasic dissolution test
PURPOSEBiowaivers based on BCS class can be used to establish therapeutic equivalence based on dissolution tests.
The objective of the present study was to compare a biphasic dissolution system with compendial methods in examining the in vitro performance of metronidazole drug products.
We hypothesized that where in vitro equivalence was not achieved in compendial methods, the partitioning profile to the organic phase in the biphasic system could signal bioequivalence among the drug products and comparator pharmaceutical product (CPP).
CONCLUSIONSRESULTS
None of the tested metronidazole products were in vitro equivalent to the CPP or to other manufacturers in compendial buffer. The tested metronidazole products followed a similar pattern than that obtained in the compendial buffer in the aqueous phase of the biphasic system.
METHODSThe in vitro performance of metronidazole drug products marketed in different countries of the Americas was compared to the US comparator pharmaceutical product (CPP) to determine if they met in vitro bioequivalence criteria.
Disintegration test
The test was performed according to USP general chapter <701>. Disintegration time was measured in a disintegration tester (Eureka, Germany) using 900 mL of phosphate buffer pH 6.8 at 37 ± 2 °C as medium. Six tablets of each drug product were tested.
Dissolution test
Five commercial metronidazole tablets were tested in compendial Simulated Intestinal Fluid (SIF), as well as in physiological buffer capacity (5mM phosphate buffer at pH 6.8, 900 mL). The tablets were also tested in a biphasic dissolution system in which the aqueous layer was composed of 200 mL of 5 mM phosphate buffer (pH 6.8) with 100 mL of n-octanol on top.
REFERENCES AND ACKNOWLEDGEMENTSAmaral Silva, D.; Al-Gousous, J.; Davies, N. M.; Bou Chacra, N.; Webster, G. K.; Lipka, E.; Amidon, G. L.; Löbenberg, R. Biphasic Dissolution as an Exploratory Method during Early Drug Product Development. Pharmaceutics 2020, 12 (5), 420. https://doi.org/10.3390/pharmaceutics12050420.
Mudie, D. M.; Shi, Y.; Ping, H.; Gao, P.; Amidon, G. L.; Amidon, G. E. Mechanistic Analysis of Solute Transport in an in Vitro Physiological Two-Phase Dissolution Apparatus. Biopharm. Drug Dispos. 2012, 33, 378–402. https://doi.org/10.1002/bdd.1803.
Daniela Amara Silva is supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Breast Cancer Research program, under Award No. W81XWH-17-1-0470. Opinions, interpretations, conclusions and recommendations are those of the author and not necessarily endorsed by the Department of Defense
• None of the tested metronidazole products demonstrated in vitro equivalence to the CPP in the monophasic dissolution methods, i.e. SIF and physiological buffer capacity.
• The monophasic aqueous systems seem to be overdiscriminating.
• The correlation of the organic phase of the biphasic system showed a similar partitioning pattern for all the generic drug products and CPP, which could indicate in vitro equivalence.
• The application of biphasic dissolution to highly soluble drug and formulations has beneficial attributes to estimate the in vivo behavior and performance.
• Further in vitro studies with other products are needed to confirm and refine these findings.
% D
issol
ved
Time
BCS-based biowaiver using biphasic dissolution test Daniela Amaral Silva1, Katherine Curo Melo1,2, Neal M. Davies1, Nadia Bou-Chacra2, Humberto G. Ferraz2, Raimar Löbenberg1. 1Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada. 2Faculty of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil.
Interchangeable/bioequivalent?Surrogate test
PRODUCT DISINTEGRATIONTime (min) SD
FLAGYL-USP (CPP) 5.32 0.43FLAGYL-MEXICO 18.27 0.58
FLAGENASE 10.16 0.07COLPOFILIN 0.60 0.22
METRAL 13.32 0.78
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Table 1. Disintegration time of different commercially available metronidazole IR tablets
Figure 1. Dissolution profiles of metronidazole formulations in SIF (solid lines) and low buffer capacity phosphate buffer (5mM – dashed lines).
Figure 2. Biphasic dissolution profiles of metronidazole formulations in the aqueous (dashed lines) and organic phases (solid lines).
Flagyl-USP, Flagyl-Mex, Flagenase, Colpofilin,
Metral
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This was not the case for the organic phase partition profiles. All the tested products had a good correlation to the CPP, which could indicate in vitro equivalence between these products. This could potentially allow for a biowaiver application.
Figure 3. Correlation between the comparator pharmaceutical product (CPP) and generic products of the amount partitioned to the organic phase. Only data after full tablet disintegration were used. Flagyl-Mex, Flagenase, Colpofilin, Metral
FLAGYL-USP (CPP)FLAGYL-MEXICO 0.996
FLAGENASE 0.95COLPOFILIN 0.95
METRAL 0.97
Table 2. Correlation coefficient (R2) between the CPP and generic products
Intestinallumen
Blood stream
Epithelial cells
Stomach residence time for half emptying à up to 17
minutes
