Amorphous mixtures of albendazole with carboxylic acids and evaluation of their anthelmintic activity

The purpose of the research is modification of albendazole (ABZ) properties due to the formation amorphous mixtures with carboxylic acids and evaluation of their anthelmintic activity.

Materials and methods. Amorphous mixtures of ABZ with carboxylic acids (citric, succinic, p-toluenesulfonic and oxalic) were obtained according to the method described by Shete A.S. et al. (2019) with minor modification and expansion of the spectrum of carboxylic acids. The obtained amorphous mixtures were characterized by water solubility and ABZ content by high-performance liquid chromatography. IR spectroscopy method was used to prove the formation of target products. The anthelmintic activity of ABZ amorphous mixtures with organic acids in 1 : 1 ratio was studied on 80 white mice experimentally infected with Trichinella spiralis. Various mixtures of anthelmintic were administered into the stomach of mice of experimental groups at a dose of 2 mg/kg of active substance (AS). ABZ substance was used as a basic drug at a dose of 2 mg/kg of AS. The animals of the control group did not receive the drugs. The animals were sacrificed by cervical dislocation on the fourth day after drugs administration. The anthelmintic activity of the drugs was assessed based on the results of the helminthological necropsy of the mice intestines, and the efficacy was calculated according to the “control test”.

Results and discussion. An increase in the solubility of the obtained amorphous mixtures of ABZ with carboxylic acids was established, the highest indices were noted for mixtures of ABZ with citric and para-toluenesulfonic acids. IR analysis confirmed the formation of salt-like products. It was established that the efficacy of amorphous mixtures of ABZ is higher than the activity of the basic drug (31.22%) in experimental trichinellosis, in particular, salt forms of albendazole with p-toluenesulfonic acid obtained after joint grinding showed 69.25%; amorphous mixtures with citric acid obtained after boiling in isopropanol showed 68.24% activity. Thus, when ABZ is modified with organic acids, its physicochemical properties change and its biological activity changes towards an increase.

1. Arkhipov I. A., Varlamova A. I., Odoevskaya I. M. Methodological recommendations for testing and assessment of efficiency of medications against trichinellosis and hymenolepidosis in laboratory model. Rossiyskiy parazitologicheskiy zhurnal = Russian Journal of Parasitology. 2019; 13 (2): 58 63. (In Russ.) https://doi.org/10.31016/1998-8435 2019-13-2-58-63

2. Khalikov S. S., Dushkin A. V. Methods of improving the solubility of anthelmintic drugs. Khimiko farmatsevticheskiy zhurnal = Pharmaceutical Chemistry Journal. 2020; 54 (5): 33-37. (In Russ.) https://doi.org/10.30906/0023-1134-2020-54-5-33-37

3. Abhilash K. R., Balasaradhi K., Ramesh Y. Formulation and evaluation of albendazole nanoparticle. Journal of Drug Delivery and T herapeutics. 2019; 9 (1-s): 16-22. https://doi.org/10.22270/jddt.v9i1-s.2239

4. Babu N. J., Nanga A. Solubility Advantage of Amorphous Drugs and Pharmaceutical Cocrystals. Crystal Growth & Design. 2011; 11 (7): 2662–2679. https://doi.org/10.1021/cg200492w

5. Bongioanni A., Araújo B. S., de Oliveira Y. S., Longhi M. R., Ayala A., Garnero C. Improving properties of albendazole desmotropes by supramolecular systems with maltodextrin and glutamic acid. AAPS PharmSciTech. 2018; 19: 1468–1476. https://doi.org/10.1208/s12249-018-0952-0

6. Bongioanni A., Bueno M. S., Abraham-Miranda J., Chattah A. K., Ayala A. P., Longhi M. R., Garnero C. Investigating a Soluble Pharmaceutical Salt: Albendazole Hydrochloride. Crystal Growth & Design. 2019; 19 (8): 4538-4545. https://doi.org/10.1021/acs.cgd.9b00348

7. Bongioanni A., Sancho M. I., Bueno M. S., Longhi M. R., Chattah A. K. Binary systems of albendazole desmotropes with amino-acids: Experimental and theoretical studies. Journal of Molecular Liquids. 2021; 340: 117282. https://doi.org/10.1016/j.molliq.2021.117282

8. Castro L. S., Kviecinski M. R., Ourique F., Parisotto E. B., Grinevicius V. M., Correia J. F., Wilhelm Filho D., Pedrosa R. C. Albendazole as a promising molecule for tumor control. Redox Biology. 2016; 10: 90-99. https://doi.org/10.1016/j.redox.2016.09.013

9. Cerutti J. P., Quevedo M. A., Buhlman N., Longhi M. R., Zoppi A. Synthesis and characterization of supramolecular systems containing nifedipine, β-cyclodextrin and aspartic acid. Carbohydrate Polymers. 2019; 205: 480-487. https://doi.org/10.1016/j.carbpol.2018.10.038

10. Chattah A. K., Pfund L. Y., Zoppi A., Longhi M. R., Garnero C. Toward novel antiparasitic formulations: Complexes of Albendazole desmotropes and β-cyclodextrin. Carbohydrate Polymers. 2017; 164: 379-385. https://doi.org/10.1016/j.carbpol.2017.01.098

11. Chattah A. K., Zhang R., Mroue K. H., Pfund L. Y., Longhi M. R., Ramamoorthy A., Garnero C. Investigating albendazole desmotropes by solid state NMR spectroscopy. Molecular Pharmaceutics. 2015; 12 (3): 731-741. https://doi.org/10.1021/mp500539g

12. Codina A. V., García A., Leonardi D., Vasconi M. D., Di Masso R. J., Lamas M. C., Hinrichsen L. I. Efficacy of albendazole: β-cyclodextrin citrate in the parenteral stage of Trichinella spiralis infection. International Journal of Biological Macromolecules. 2015; 77: 203-206. https://doi.org/10.1016/j.ijbiomac.2015.02.049

13. Cook G. C. Use of benzimidazole chemotherapy in human helminthiases: Indications and efficacy. Parasitology Today. 1990; 6 (4): 133–136. https://doi.org/10.1016/0169-4758(90)90232-s

14. Fabbri J., Pensel P. E., Albani C. M., Lopez L. M., Simonazzi A., Bermudez J. M., Palma S. D., Elisson- do M. C. Albendazole solid dispersions against alveolar echinococcosis: a pharmacotechnical strategy to improve the efficacy of the drug. Parasitology. 2020; 147 (9): 1026-1031. https://doi.org/10.1017/S0031182020000670

15. Horton J. Echinococcosis and Albendazole: A Case for Suitable Treatment. The American Journal of Tropical Medicine Hygiene. 2018; 99 (4): 811-812. https://doi.org/10.4269/ajtmh.18-0609

16. Koradia D. K., Parikh H. R., Koradia H. Albendazole nanocrystals: Optimization, spectroscopic, thermal and anthelminitic studies. Journal of Drug Delivery Science and Technology. 2017; 43: 369-378. https://doi.org/10.1016/j.jddst.2017.11.003

17. Lindenberg M., Kopp S., Dressman J. B. Classification of orally administered drugs on the World Health Organization Model list of Essential Medicines according to the biopharmaceutics classification system. European Journal of Pharmaceutics and Biopharmaceutics. 2004; 58 (2): 265–278. https://doi.org/10.1016/j.ejpb.2004.03.001

18. Marriner S. Anthelmintic drugs. Veterinary Record. 1986; 118 (7): 181–184. https://doi.org/10.1136/vr.118.7.181

19. Movahedi F., Li L., Gu W., Xu Z. P. Nanoformulations of albendazole as effective anticancer and antiparasite agents. Nanomedicine. 2017; 12 (20): 2555-2574. https://doi.org/10.2217/nnm-2017-0102

20. Pensel P., Paredes A., Albani C. M., Allemandi D., Sanchez Bruni S., Palma S. D., Elissondo M. C. Albendazole nanocrystals in experimental alveolar echinococcosis: Enhanced chemoprophylactic and clinical efficacy in infected mice. Veterinary Parasitology. 2018; 251: 78-84. https://doi.org/10.1016/j.vetpar.2017.12.022

21. Pourgholami M. H., Akhter J., Wang L., Lu Y., Morris D. L. Antitumor activity of albendazole against the human colorectal cancer cell line HT 29: in vitro and in a xenograft model of peritoneal carcinomatosis. Cancer Chemotherapy and Pharmacology. 2005; 55 (5): 425–432. https://doi.org/10.1007/S00280-004-0927-6

22. Pranzo M. B., Cruickshank D., Coruzzi M., Caira M. R., Bettini R. Enantiotropically related albendazole polymorphs. Journal of Pharmaceutical Science. 2010; 99 (9): 3731-3742. https://doi.org/10.1002/jps.22072

23. Rosas M. D., Piqueras C. M., Piva G. K., Ramírez Rigo M. V., Morais Lião L., Bucalá V. Simultaneous formation of inclusion complex and microparticles containing Albendazole and β-Cyclodextrin by supercritical antisolvent co-precipitation. Journal of CO2 Utilization. 2021; 47: 101505. https://doi.org/10.1016/j.jcou.2021.101505

24. Shete A., Kumbhar B. K., Yadav A., Korpale S., Sakhare S. S., Rc Doijad R. C. Amorphous mixtures of Albendazole with carboxylic acids by cogrinding Technique: solid state characterizations and in vitro efficacy study. Journal of drug delivery. 2019; 9: 509 516. https://doi.org/10.25258/IJDDT.9.4.1

25. Siddiqua T., Habeeb A. Neurocysticercosis. Saudi Journal of Kidney Diseases and Transplantation. 2020; 31 (1): 254-258. https://doi.org/10.4103/1319-2442.279948

26. Son D. S., Lee E. S., Adunyah S. E. The Antitumor Potentials of Benzimidazole Anthelmintics as Repurposing Drugs. Immune Network. 2020; 20 (4): e29. https://doi.org/10.4110/in.2020.20.e29