Development of a granulate based on amidines with anti-infl ammatory activity

I n t r o d u c t i o n . Amidines have a fairly high biological activity. One aspect of their therapeutic action is the antiinflammatory effect. Therefore, the development of a granulate technology based on amidines with anti-inflammatory activity for subsequent dosing into enteric capsules is an issue of interest today.
A i m . To develop a granulate based on amidines with anti-inflammatory activity for subsequent dosing into enteric capsules.
M a t e r i a l s  a n d  m e t h o d s . An experimentally synthesized substance N-(naphthalene-2-yl)benzene carboximidamide and excipients: lactose monohydrate, sodium starch glycolate (Explotab®), povidone (Plasdone™ K-29/32) were used as the active substance. The granulate was obtained by pressing wet masses through. The resulting granulate was dosed into enteric capsules. The technological properties of the substance and the quality attributes of the granulate and capsules were determined according to the methods described in the State Pharmacopoeia of the Russian Federation, edition XIV (SP XIV).
R e s u l t s . According to the results of the study of technological properties, it was found that the substance has poor flowability, is quite light and bulky, the main fraction of the powder is particles up to 0.1 mm in size. To improve the flowability and reduce the hygroscopicity of the granulated material, lactose monohydrate was used as a filler. A 5% solution of Plasdone K-29/32 was chosen as a binder, which improves the dissolution and bioavailability of drugs due to the formation of water-soluble complexes. Sodium starch glycolate was used as a disintegrant. The resulting granulate was dosed into enteric capsules that meet the SP XIV requirements.
C o n c l u s i o n . A synthesis method was proposed and a substance of N-(naphthalene-2-yl)benzene carboximidamide with pharmacological activity was synthesized. Excipients were selected taking into account the properties of the substance, composition and technology of the granulate based on the previously synthesized substance N-(naphthalene-2-yl) benzene carboximidamide was developed, followed by dosing into enteric capsules, a draft specification for enteric capsules was proposed in accordance with the SP XIV requirements.

1. Kuvaeva E.V., Fedorova E.V., Yakovlev I.P., Ksenofontova G.V., Karasavidi A.O. Synthesis and biological activity of N-arylbenzamidines. Butlerov Communications. 2014;39(8):76–81. (In Russ.)

2. Kuvaeva E.V., Fedorova E.V., Ksenofontova G.V., Semakova T.L., Yakovlev I.P. N-arylbenzamidines hydrochlorides. Synthesis and structure. Drug Development & Registration. 2017;(3):108–109. (In Russ.)

3. Kuvaeva E.V., Fedorova E.V., Yakovlev I.P., Kirillova E.N., Semakova T.L. Virtual screening in search for the biological activity of novel derivatives of arybenzamidine. Pharmacy. 2015;64(8):29–32. (In Russ.)

4. Kuvaeva E.V., Kolesnik D.A., Ksenofontova G.V., Semakova T.L., Yakovlev I.P. Synthesis and structure of some N-arylbenzamidines. Drug Development & Registration. 2017;4(21):140–143. (In Russ.)

5. Brunton L.L., Hilal-Dandan R., Knollmann B.C. (2017). Goodman & Gilman’s. The Pharmacological Basis of Therapeutics. 13th ed. McGraw Hill Educ., рр. 31–55.

6. Weintraub W.S. Safety of non-steroidal antiinfl amm atory drugs. European Heart Journal. 2017;38(44):3293–3295. DOI: 10.1093/eurheartj/ehx533.

7. Mahesh G., Anil Kumar K., Reddanna P. Overview on the discovery and development of anti-infl ammatory drugs: should the focus be on synthesis or degradation of PGE2? J. Infl am. Res. 2021;14:253–263. DOI: 10.2147/JIR.S278514.

8. Fendric A.M., Pan D.E., Johnson G.E. OTC analgesics and drug interactions: clinical implications. Osteopath. Med. Prim. Care. 2008;7(2):2. DOI: 10.1186/17504732-2-2.

9. Zhurakhovskaya D.V., Loskutova E.E., Vinogradova I.A. Non-steroidal anti-infl ammatory drugs regional market research. Modern Problems of Science and Education. 2014;2:628. (In Russ.)

10. PHARMINDEX.RF. Russian Pharmaceutical Portal. URL: https://www.pharmindex.ru (accessed 04.03.2022).

11. Ushkalova E.A., Zyryanov S.K., Pereverzev A.P. (2018). Clinical Pharmacology of Non-steroidal Anti-infl ammatory Drugs: Textbook. 368 p. (In Russ.)

12. Ignatov Yu.D., Kukes V.G., Mazurov V.I. (eds.) (2010). Clinical Pharmacology of Non-steroidal Anti-infl ammatory Drugs. Moscow: GEOTAR-Media. 256 p. (In Russ.)

13. Wongrakpanich S., Wongrakpanich A., Melhado K., Rangaswami J. A comprehensive review of non-steroidal anti-infl ammatory drug use in the elderly. Aging and Disease. 2018;9(1):143–150. DOI: 10.14336/ AD.2017.0306.

14. PASS online. URL: http://www.pharmaexpert.ru/passonline/predict.php (accessed 04.03.2022).

15. State Pharmacopoeia of the Russian Federation, edition XIV. URL: https://femb.ru/record/pharmacopea14 (accessed 04.03.2022).

16. Novikova E.K., Chachin D.A., Kaukhova I.E., Minina S.A. Development and standardization of granules in hard gelatin capsules based on the composition of dry extracts of Bidens tripartita, Solidago canadensis L. and Agrimonia eupatoria herbs. Drug Development & Registration. 2018;4(25):44–48. (In Russ.)

17. Egoshina Yu.A., Potselueva L.A. Modern tablet excipients. Successes of Modern Natural Science. 2009;10:30–33. (In Russ.)

18. Van der Merwe J., Steenekamp J., Steyn D., Hamman J. The role of functional excipients in solid oral dosage forms to overcome poor drug dissolution and bioavailability. Pharmaceutics. 2020;12(5):393. DOI: 10.3390/pharmaceutics12050393.

19. Smekhova I.E., Vainshtein V.A., Ladutko Y.M., Druzhininskaya O.V., Tureckova N.N. Disintegrants and their infl uence on the dissolution of substances of biopharmaceutical classifi cation system classes. Drug Development & Registration. 2018;4(25):62–72. (In Russ.)