Developing Composition and Technology of Ethylthiobenzimidazole Fumarate Matrix Tablets According to Specified Release Profile

INTRODUCTION. Ethylthiobenzimidazole fumarate (ETBIF) is a new actoprotector and adaptogenic active pharmaceutical ingredient (API). ETBIF was found to be effective given in short intervals; side effects related to ETBIF stomach solubility are known. Therefore, it is essential to develop a matrix dosage form with a specific release profile that can neutralize these side effects, prolong dosing intervals, and increase treatment compliance.

AIM. This study aimed to develop composition and production technology of ETBIF matrix tablets in accordance with a specified release profile (total release within 12 hours; not more than 50% of ETBIF released in acidic environment within the first two hours; the rest evenly released over the next 10 hours in the intestine-simulating environment).

MATERIALS AND METHODS. The study examined ETBIF (API) as well as hydroxypropylmethylcellulose (hypromellose) and ethyl cellulose-based matrix ETBIF tablets. Mechanical properties of the tablets were examined, in particular hardness and friability. ETBIF release profiles were studied in different phosphate buffer solutions (pH 1.2, 4.5, and 6.8) using a dissolution tester and UV spectrometry.

RESULTS. The authors studied ETBIF release kinetics from matrix systems with various matrix-forming components of different origin. Hypromellose-based compounds enabled prolonged ETBIF release (90% after 12 h). Ethyl cellulose compounds showed 60 to 90% release, with API mostly releasing in acidic environment.

Adding an acid does not affect ETBIF release from matrix tablets.

CONCLUSIONS. A composition of matrix tablets has been developed that meets the specified release profile. Hypromellose-based tablets showed the most complete and uniform release of the substance in an environment simulating gastrointestinal tract. Adding an acid does not affect ETBIF release from matrix tablets, despite its increased solubility in the acidic environment.

1. Okovityj SV, Radko SV, Dulepov AD, Yuskovets VN. Antihypoxic and act-protective agent based on 2-(ethylsulfanyl)-1h-Benzimidazol-3-y (2e)-3carboxyprop-2-enoate. Patent of the Russian Federation № 2673338; 2017 (In Russ.). EDN: LVGMNC

2. Bolotina YuD, Bolotova VTs. Study of the antihypoxic activity of a new benzimidazole derivative with dicarboxylic acid under histotoxic hypoxia. Journal Biomed. 2020;16(3):102–5 (In Russ.). https://doi.org/10.33647/2074-5982-16-3-102-105

3. Bolotova VTs, Bolotina YuD, Shustov ЕB. Effect of ethylthiobenzimidazole fumarate on the physical performance of mice under conditions of simultaneous hypoxic and hyperthermal exposure. Journal Biomed. 2021;17(3E):139–43 (In Russ.). https://doi.org/10.33647/2713-0428-17-3E-139-143

4. Dulepov AD, Radko SV. Acute toxicity and effect on physical performance of a new derivative of ethylthiobenzimidazole with a single and course administration. Fundamental science in modern medicine — 2018. Collection of materials of the satellite remote scientific and practical conference of students and young scientists. Minsk; 2018. P. 109–13 (In Russ.).

5. Kasymov ID, Marchenko AL, Basevich AV, Valeeva ME. Influence of technological process parameters on microcapsulation of substances with unsatisfactory technological properties. Drug Development & Registration. 2023;12(4): 146–54 (In Russ.). https://doi.org/10.33380/2305-20662023-12-4-1574

6. Lyzikov AN, Pitkevich ES, Melnik SN. Prospects for clinical application of antihypoxant “Bеmithyl” (literature review). Health and Ecology Issues. 2011;(1):7–14 (In Russ.). https://doi.org/10.51523/2708-6011.2011-8-1-1

7. Vergeichik TH, Linnikova VA, Guskova GB. UV spectrophotometry application for identification of conditions for metaprote extraction from water solutions. Pharmacy and Pharmacology. 2014;2(5(6)):11–6 (In Russ.). https://doi.org/10.19163/2307-9266-2014-2-5(6)-11-16

8. Vergeichik TH, Linnikova VA, Guskova GB, Sargsyan MS. Detection and identification metaprote in the liver and kidneys. Journal of scientific articles «Health & Education Millennium». 2017;19(8):210–4 (In Russ.). EDN: YORPFJ

9. Demina NB. Current trends in the development of technologies for matrix formulations with modified release (review). Pharm Chem J. 2016;50(7):475–80. https://doi.org/10.1007/s11094-016-1472-4

10. Anurova MN, Bakhrushina EO, Demina NB. Review of contemporary gel-forming agents in the technology of dosage forms. Pharm Chem J. 2015;49(9):627–34. https://doi.org/10.1007/s11094-015-1342-5

11. Agarwal P, Semimul A. A comprehensive review on sustained release matrix tablets: a promising dosage form. Univ J Pharm Res. 2018;3(6):49–54. https://doi.org/10.22270/ujpr.v3i6.222

12. Nandhakumar S, Sugreevudu G, Harikrishnan N. Formulation design and evaluation of extended-release tablets of oxybutynin for effective management of overactive bladder syndrome. Research J Pharm Tech. 2021;14(12):6558–64. https://doi.org/10.52711/0974-360X.2021.01135

13. Alkhodri A, Suslina SN. Development of celecoxib granules for manufacturing of prolonged release celecoxib capsules and tablets. Drug Development & Registration. 2022;11(1):68–73. (In Russ.). https://doi.org/10.33380/2305-2066-2022-11-1-68-73

14. Kotsur YuM, Flisyuk EV, Sidorov KO, et al. Study of the effect of matrix-forming polymers on the release rate of sodium 4,4’-(propanediamido) dibenzoate from tablets. Drug Development & Registration. 2023;12(4):91–5 (In Russ.). https://doi.org/10.33380/23052066-2023-12-4-1579

15. Filippova NI, Vainshtein VA, Son AV, Minina SA. Regulation of ibuprofen release rate from matrix tablets. Drug Development & Registration. 2017;(1):58–64 (In Russ.). EDN: YKPHCB

16. Kasymov ID, Basevich AV. Study of the technological properties of excipients in the development of the composition of orally dispersible tablets. Drug Development & Registration. 2021;10(4):46–53 (In Russ.). https://doi.org/10.33380/2305-2066-2021-10-4(1)-46-53