Exploring Bioequivalence of Dexketoprofen Trometamol Drug Products with the Gastrointestinal Simulator (GIS) and Precipitation Pathways Analyses
The present work aimed to explain the differences in oral performance in fasted humans who were categorized into groups based on the three different drug product formulations of dexketoprofen trometamol (DKT) salt—Using a combination of in vitro techniques and pharmacokinetic analysis. The...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2019-03-01
|
| Series: | Pharmaceutics |
| Subjects: | |
| Online Access: | http://www.mdpi.com/1999-4923/11/3/122 |
| _version_ | 1798043643545649152 |
|---|---|
| author | Marival Bermejo Gislaine Kuminek Jozef Al-Gousous Alejandro Ruiz-Picazo Yasuhiro Tsume Alfredo Garcia-Arieta Isabel González-Alvarez Bart Hens Gregory E. Amidon Nair Rodriguez-Hornedo Gordon L. Amidon Deanna Mudie |
| author_facet | Marival Bermejo Gislaine Kuminek Jozef Al-Gousous Alejandro Ruiz-Picazo Yasuhiro Tsume Alfredo Garcia-Arieta Isabel González-Alvarez Bart Hens Gregory E. Amidon Nair Rodriguez-Hornedo Gordon L. Amidon Deanna Mudie |
| author_sort | Marival Bermejo |
| collection | DOAJ |
| description | The present work aimed to explain the differences in oral performance in fasted humans who were categorized into groups based on the three different drug product formulations of dexketoprofen trometamol (DKT) salt—Using a combination of in vitro techniques and pharmacokinetic analysis. The non-bioequivalence (non-BE) tablet group achieved higher plasma Cmax and area under the curve (AUC) than the reference and BE tablets groups, with only one difference in tablet composition, which was the presence of calcium monohydrogen phosphate, an alkalinizing excipient, in the tablet core of the non-BE formulation. Concentration profiles determined using a gastrointestinal simulator (GIS) apparatus designed with 0.01 N hydrochloric acid and 34 mM sodium chloride as the gastric medium and fasted state simulated intestinal fluids (FaSSIF-v1) as the intestinal medium showed a faster rate and a higher extent of dissolution of the non-BE product compared to the BE and reference products. These in vitro profiles mirrored the fraction doses absorbed in vivo obtained from deconvoluted plasma concentration–time profiles. However, when sodium chloride was not included in the gastric medium and phosphate buffer without bile salts and phospholipids were used as the intestinal medium, the three products exhibited nearly identical concentration profiles. Microscopic examination of DKT salt dissolution in the gastric medium containing sodium chloride identified that when calcium phosphate was present, the DKT dissolved without conversion to the less soluble free acid, which was consistent with the higher drug exposure of the non-BE formulation. In the absence of calcium phosphate, however, dexketoprofen trometamol salt dissolution began with a nano-phase formation that grew to a liquid–liquid phase separation (LLPS) and formed the less soluble free acid crystals. This phenomenon was dependent on the salt/excipient concentrations and the presence of free acid crystals in the salt phase. This work demonstrated the importance of excipients and purity of salt phase on the evolution and rate of salt disproportionation pathways. Moreover, the presented data clearly showed the usefulness of the GIS apparatus as a discriminating tool that could highlight the differences in formulation behavior when utilizing physiologically-relevant media and experimental conditions in combination with microscopy imaging. |
| first_indexed | 2024-04-11T22:51:56Z |
| format | Article |
| id | doaj.art-8fa34fe3d1fe4e7e93dffe3265f92e6e |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-04-11T22:51:56Z |
| publishDate | 2019-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-8fa34fe3d1fe4e7e93dffe3265f92e6e2022-12-22T03:58:33ZengMDPI AGPharmaceutics1999-49232019-03-0111312210.3390/pharmaceutics11030122pharmaceutics11030122Exploring Bioequivalence of Dexketoprofen Trometamol Drug Products with the Gastrointestinal Simulator (GIS) and Precipitation Pathways AnalysesMarival Bermejo0Gislaine Kuminek1Jozef Al-Gousous2Alejandro Ruiz-Picazo3Yasuhiro Tsume4Alfredo Garcia-Arieta5Isabel González-Alvarez6Bart Hens7Gregory E. Amidon8Nair Rodriguez-Hornedo9Gordon L. Amidon10Deanna Mudie11Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USADepartment of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USADepartment of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USADepartment Engineering Pharmacy Section, Miguel Hernandez University, San Juan de Alicante, 03550 Alicante, SpainDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USAService on Pharmacokinetics and Generic Medicines, Division of Pharmacology and Clinical Evaluation, Department of Human Use Medicines, Spanish Agency for Medicines and Health Care Products, 28022 Madrid, SpainDepartment Engineering Pharmacy Section, Miguel Hernandez University, San Juan de Alicante, 03550 Alicante, SpainDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USADepartment of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USADepartment of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USADepartment of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USADepartment of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USAThe present work aimed to explain the differences in oral performance in fasted humans who were categorized into groups based on the three different drug product formulations of dexketoprofen trometamol (DKT) salt—Using a combination of in vitro techniques and pharmacokinetic analysis. The non-bioequivalence (non-BE) tablet group achieved higher plasma Cmax and area under the curve (AUC) than the reference and BE tablets groups, with only one difference in tablet composition, which was the presence of calcium monohydrogen phosphate, an alkalinizing excipient, in the tablet core of the non-BE formulation. Concentration profiles determined using a gastrointestinal simulator (GIS) apparatus designed with 0.01 N hydrochloric acid and 34 mM sodium chloride as the gastric medium and fasted state simulated intestinal fluids (FaSSIF-v1) as the intestinal medium showed a faster rate and a higher extent of dissolution of the non-BE product compared to the BE and reference products. These in vitro profiles mirrored the fraction doses absorbed in vivo obtained from deconvoluted plasma concentration–time profiles. However, when sodium chloride was not included in the gastric medium and phosphate buffer without bile salts and phospholipids were used as the intestinal medium, the three products exhibited nearly identical concentration profiles. Microscopic examination of DKT salt dissolution in the gastric medium containing sodium chloride identified that when calcium phosphate was present, the DKT dissolved without conversion to the less soluble free acid, which was consistent with the higher drug exposure of the non-BE formulation. In the absence of calcium phosphate, however, dexketoprofen trometamol salt dissolution began with a nano-phase formation that grew to a liquid–liquid phase separation (LLPS) and formed the less soluble free acid crystals. This phenomenon was dependent on the salt/excipient concentrations and the presence of free acid crystals in the salt phase. This work demonstrated the importance of excipients and purity of salt phase on the evolution and rate of salt disproportionation pathways. Moreover, the presented data clearly showed the usefulness of the GIS apparatus as a discriminating tool that could highlight the differences in formulation behavior when utilizing physiologically-relevant media and experimental conditions in combination with microscopy imaging.http://www.mdpi.com/1999-4923/11/3/122gastrointestinal absorptiondexketoprofengastrointestinal simulatormicroscopy imagingliquid–liquid phase separationoral absorptionin vitro dissolution |
| spellingShingle | Marival Bermejo Gislaine Kuminek Jozef Al-Gousous Alejandro Ruiz-Picazo Yasuhiro Tsume Alfredo Garcia-Arieta Isabel González-Alvarez Bart Hens Gregory E. Amidon Nair Rodriguez-Hornedo Gordon L. Amidon Deanna Mudie Exploring Bioequivalence of Dexketoprofen Trometamol Drug Products with the Gastrointestinal Simulator (GIS) and Precipitation Pathways Analyses Pharmaceutics gastrointestinal absorption dexketoprofen gastrointestinal simulator microscopy imaging liquid–liquid phase separation oral absorption in vitro dissolution |
| title | Exploring Bioequivalence of Dexketoprofen Trometamol Drug Products with the Gastrointestinal Simulator (GIS) and Precipitation Pathways Analyses |
| title_full | Exploring Bioequivalence of Dexketoprofen Trometamol Drug Products with the Gastrointestinal Simulator (GIS) and Precipitation Pathways Analyses |
| title_fullStr | Exploring Bioequivalence of Dexketoprofen Trometamol Drug Products with the Gastrointestinal Simulator (GIS) and Precipitation Pathways Analyses |
| title_full_unstemmed | Exploring Bioequivalence of Dexketoprofen Trometamol Drug Products with the Gastrointestinal Simulator (GIS) and Precipitation Pathways Analyses |
| title_short | Exploring Bioequivalence of Dexketoprofen Trometamol Drug Products with the Gastrointestinal Simulator (GIS) and Precipitation Pathways Analyses |
| title_sort | exploring bioequivalence of dexketoprofen trometamol drug products with the gastrointestinal simulator gis and precipitation pathways analyses |
| topic | gastrointestinal absorption dexketoprofen gastrointestinal simulator microscopy imaging liquid–liquid phase separation oral absorption in vitro dissolution |
| url | http://www.mdpi.com/1999-4923/11/3/122 |
| work_keys_str_mv | AT marivalbermejo exploringbioequivalenceofdexketoprofentrometamoldrugproductswiththegastrointestinalsimulatorgisandprecipitationpathwaysanalyses AT gislainekuminek exploringbioequivalenceofdexketoprofentrometamoldrugproductswiththegastrointestinalsimulatorgisandprecipitationpathwaysanalyses AT jozefalgousous exploringbioequivalenceofdexketoprofentrometamoldrugproductswiththegastrointestinalsimulatorgisandprecipitationpathwaysanalyses AT alejandroruizpicazo exploringbioequivalenceofdexketoprofentrometamoldrugproductswiththegastrointestinalsimulatorgisandprecipitationpathwaysanalyses AT yasuhirotsume exploringbioequivalenceofdexketoprofentrometamoldrugproductswiththegastrointestinalsimulatorgisandprecipitationpathwaysanalyses AT alfredogarciaarieta exploringbioequivalenceofdexketoprofentrometamoldrugproductswiththegastrointestinalsimulatorgisandprecipitationpathwaysanalyses AT isabelgonzalezalvarez exploringbioequivalenceofdexketoprofentrometamoldrugproductswiththegastrointestinalsimulatorgisandprecipitationpathwaysanalyses AT barthens exploringbioequivalenceofdexketoprofentrometamoldrugproductswiththegastrointestinalsimulatorgisandprecipitationpathwaysanalyses AT gregoryeamidon exploringbioequivalenceofdexketoprofentrometamoldrugproductswiththegastrointestinalsimulatorgisandprecipitationpathwaysanalyses AT nairrodriguezhornedo exploringbioequivalenceofdexketoprofentrometamoldrugproductswiththegastrointestinalsimulatorgisandprecipitationpathwaysanalyses AT gordonlamidon exploringbioequivalenceofdexketoprofentrometamoldrugproductswiththegastrointestinalsimulatorgisandprecipitationpathwaysanalyses AT deannamudie exploringbioequivalenceofdexketoprofentrometamoldrugproductswiththegastrointestinalsimulatorgisandprecipitationpathwaysanalyses |