Physicochemical considerations in the formulation development of silicone elastomer vaginal rings releasing 5-nitroimidazole drugs for the treatment of bacterial vaginosis
Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved..
Bacterial vaginosis (BV) is a common dysbiosis of the human vaginal microbiota characterized by depletion of hydrogen peroxide and lactic acid-producing Lactobacillus bacteria and an overgrowth of certain facultative anaerobic bacteria. Although short-term cure rates following treatment with frontline antibiotics (most notably oral metronidazole (MNZ), clindamycin vaginal cream, and MNZ vaginal gel) are generally high, longer-term recurrence rates are an issue. The development of vaginal formulations offering continuous/sustained administration of antibiotic drugs over one or more weeks might prove useful in reducing recurrence. Here, we report the manufacture and preclinical testing of matrix-type vaginal rings offering sustained release of four 5-nitroimidazole antimicrobial drugs either being used clinically or having potential in treatment of BV - MNZ, tinidazole (TNZ), secnidazole (SNZ) and ornidazole (ONZ). All four drugs showed good compatibility with a medical-grade addition-cure silicone elastomer based upon thermal analysis experiments, and matrix-type rings containing 250 mg (3.125 %w/w) of each drug were successfully manufactured by reaction injection molding. 28-day in vitro drug release studies demonstrated root-time kinetics, with daily release rates of 25, 22, 9 and 6 mg/day½ for SNZ, ONZ, MNZ and TNZ, respectively. The rank order of drug release from rings correlated with the simple molecular permeability parameter S/V, where S is the measured drug solubility in silicone fluid and V is the drug molecular volume. The relative merits of SNZ and ONZ over MNZ (the current reference treatment) are discussed. The data support development of vaginal rings for sustained release of 5-nitroimidazole compounds for treatment of BV.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:644 |
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| Enthalten in: |
International journal of pharmaceutics - 644(2023) vom: 25. Sept., Seite 123296 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhao, Xinyu [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 12.09.2023 Date Revised 12.09.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ijpharm.2023.123296 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Zhao, Xinyu |e verfasserin |4 aut | |
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| 520 | |a Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved. | ||
| 520 | |a Bacterial vaginosis (BV) is a common dysbiosis of the human vaginal microbiota characterized by depletion of hydrogen peroxide and lactic acid-producing Lactobacillus bacteria and an overgrowth of certain facultative anaerobic bacteria. Although short-term cure rates following treatment with frontline antibiotics (most notably oral metronidazole (MNZ), clindamycin vaginal cream, and MNZ vaginal gel) are generally high, longer-term recurrence rates are an issue. The development of vaginal formulations offering continuous/sustained administration of antibiotic drugs over one or more weeks might prove useful in reducing recurrence. Here, we report the manufacture and preclinical testing of matrix-type vaginal rings offering sustained release of four 5-nitroimidazole antimicrobial drugs either being used clinically or having potential in treatment of BV - MNZ, tinidazole (TNZ), secnidazole (SNZ) and ornidazole (ONZ). All four drugs showed good compatibility with a medical-grade addition-cure silicone elastomer based upon thermal analysis experiments, and matrix-type rings containing 250 mg (3.125 %w/w) of each drug were successfully manufactured by reaction injection molding. 28-day in vitro drug release studies demonstrated root-time kinetics, with daily release rates of 25, 22, 9 and 6 mg/day½ for SNZ, ONZ, MNZ and TNZ, respectively. The rank order of drug release from rings correlated with the simple molecular permeability parameter S/V, where S is the measured drug solubility in silicone fluid and V is the drug molecular volume. The relative merits of SNZ and ONZ over MNZ (the current reference treatment) are discussed. The data support development of vaginal rings for sustained release of 5-nitroimidazole compounds for treatment of BV | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Bacterial vaginosis | |
| 650 | 4 | |a Intravaginal ring | |
| 650 | 4 | |a Multipurpose prevention technologies (MPT) | |
| 650 | 4 | |a Sustained release | |
| 650 | 7 | |a 4-nitroimidazole |2 NLM | |
| 650 | 7 | |a Y8U32AZ5O7 |2 NLM | |
| 650 | 7 | |a Silicone Elastomers |2 NLM | |
| 650 | 7 | |a Delayed-Action Preparations |2 NLM | |
| 650 | 7 | |a secnidazole |2 NLM | |
| 650 | 7 | |a R3459K699K |2 NLM | |
| 650 | 7 | |a Metronidazole |2 NLM | |
| 650 | 7 | |a 140QMO216E |2 NLM | |
| 650 | 7 | |a Anti-Bacterial Agents |2 NLM | |
| 650 | 7 | |a Tinidazole |2 NLM | |
| 650 | 7 | |a 033KF7V46H |2 NLM | |
| 650 | 7 | |a Ornidazole |2 NLM | |
| 650 | 7 | |a 62XCK0G93T |2 NLM | |
| 700 | 1 | |a Boyd, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Dallal Bashi, Yahya H |e verfasserin |4 aut | |
| 700 | 1 | |a McCoy, Clare F |e verfasserin |4 aut | |
| 700 | 1 | |a Karl Malcolm, R |e verfasserin |4 aut | |
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