THE DEVELOPMENT AND STUDY OF THE TOXICITY OF SUPPOSITORIES WITH A MODIFIED SUBSTANCE OF INTERFERON ALFA-2B

MARIA N. ANUROVA; ELENA O. BAKHRUSHINA; MARINA M. SHUMKOVA; NATALIA B. DEMINA; IVAN I. KRASNYUK

doi:10.22159/ijap.2023v15i2.46368

Authors

MARIA N. ANUROVA Department of Pharmaceutical Technology, A. P. Nelyubin Institute of Pharmacy, Sechenov University, Moscow, Russia
ELENA O. BAKHRUSHINA Department of Pharmaceutical Technology, A. P. Nelyubin Institute of Pharmacy, Sechenov University, Moscow, Russia https://orcid.org/0000-0001-8695-0346
MARINA M. SHUMKOVA Department of Pharmaceutical Technology, A. P. Nelyubin Institute of Pharmacy, Sechenov University, Moscow, Russia https://orcid.org/0000-0002-4448-2588
NATALIA B. DEMINA Department of Pharmaceutical Technology, A. P. Nelyubin Institute of Pharmacy, Sechenov University, Moscow, Russia
IVAN I. KRASNYUK Department of Pharmaceutical Technology, A. P. Nelyubin Institute of Pharmacy, Sechenov University, Moscow, Russia

DOI:

https://doi.org/10.22159/ijap.2023v15i2.46368

Keywords:

Cytotoxicity, Interferon alfa-2b, Peginterferon, Specific activity, Suppositories

Abstract

Objective: To develop a stable composition with the substance of PEGylated interferon alfa-2b, to study technological and biopharmaceutical characteristics of the dosage form, and to conduct preclinical studies on the chronic toxicity and local irritating effect.

Methods: Solid fats Witepsol® H15, Witepsol® W 35, Suppocire® BS2X, and Suppocire® BM brands were used as the suppository bases. Polysorbate 80 was used as an emulsifier. Citric acid, ascorbic acid, sodium tetraborate, lactic acid, ethylenediaminetetetraacetic acid, tocopherol acetate was also introduced into the experimental samples. Fourteen experimental samples were screened for biological and technological indicators. Preclinical studies were performed for the optimal composition on the indicators of chronic toxicity and local irritant effect.

Results: The study examined the cytotoxic effects on the Vero cell line of selected suppository bases and excipients, namely, pH regulators and antioxidants. With excipients that did not have cytotoxicity we obtained suppository compositions with the following quality indicators: cytotoxicity, specific activity of interferon, time of complete deformation of suppositories and their melting temperature. A total of 14 compositions were studied, of which 5 were selected on the basis of the results for the study of stability. Only one composition turned out to be stable for the time studied.

Conclusion: The most stable in terms of “specific activity” was sample 7, its composition: Witepsol® H15/W35 70/30, polysorbate-80 0.15%, ethylenediaminetetraacetic acid (EDTA) 0.15%, sodium tetraborate 0.15%, tocopherol acetate 3.0%. Preclinical studies, that showed the absence of chronic toxicity and local irritant effect, were performed for this composition.

Downloads

Download data is not yet available.

References

Afanasev SS, Aleshkin VA, Feklisova LV, Rubal’skii OV, Davydkin VIu. Interferon-based immunobiological preparations. An outlook of their use in the treatment of patients with infections. Vestn Ross Akad Med Nauk. 2003;1(1):44-8. PMID 12608085.

Hu Y, Ye YZ, Ye LJ, Wang XH, Yu H. Efficacy and safety of interferon alpha-2b versus pegylated interferon alpha-2a monotherapy in children with chronic hepatitis B: a real-life cohort study from Shanghai, China. World J Pediatr. 2019;15(6):595-600. doi: 10.1007/s12519-019-00303-w, PMID 31487005.

Ye YZ, Dou YL, Hao JH, Zhou L, Lin AW, Wang SN. Efficacy and safety of interferon α-2b spray for herpangina in children: A randomized, controlled trial. Int J Infect Dis. 2021;107:62-8. doi: 10.1016/j.ijid.2021.04.049, PMID 33878461.

Lin H, Huang L, Zhou J, Lin K, Wang H, Xue X. Efficacy and safety of interferon-α2b spray in the treatment of hand, foot, and mouth disease: a multicenter, randomized, double-blind trial. Arch Virol. 2016;161(11):3073-80. doi: 10.1007/s00705-016-3012-7, PMID 27518403.

Gao D, He M, Xu Q, Huang D, Wei S, Tian Y. Neuromyelitis optica spectrum disorder occurred after interferon alpha therapy in malignant melanoma. Mult Scler Relat Disord. 2019;32:33-6. doi: 10.1016/j.msard.2019.04.023, PMID 31030016.

Patel JN, Walko CM. Sylatron: a pegylated interferon for use in melanoma. Ann Pharmacother. 2012;46(6):830-8. doi: 10.1345/aph.1Q791, PMID 22619474.

Wong GL, Chan HL, Loo CK, Hui YT, Fung JY, Cheung D. Change in treatment paradigm in people who previously injected drugs with chronic hepatitis C in the era of direct-acting antiviral therapy. J Gastroenterol Hepatol. 2019;34(9):1641-47. doi: 10.1111/jgh.14622, PMID 30707777.

Kolb Maurer A, Sunderkotter C, Kukowski B, Meuth SG. Members of an expert meeting. An update on Peginterferon beta-1a Management in Multiple Sclerosis: results from an interdisciplinary Board of German and Austrian Neurologists and dermatologists. BMC Neurol. 2019;19(1):130. doi: 10.1186/s12883-019-1354-y, PMID 31202258.

Chen X, Li T, Wang FJ, Shang CG, Zhang X, Bai HH. Changes of local vaginal immune regulation in rats infected with vulvovaginal candidiasis. Zhonghua Fu Chan Ke Za Zhi. 2019;54(5):330-7. doi: 10.3760/cma.j.issn.0529-567x.2019.05.008, PMID 31154715.

Kalyuzhin OV, Ponezheva ZB, Kupchenko AN, Shuvalov AN, Guseva TS, Parshina OV. Clinical and interferon-modulating efficacy of a combination of rectal and topical dosage forms of interferon-α2b in acute respiratory infections. Ter Arkh. 2018;90(11):48-54. doi: 10.26442/terarkh2018901148-54, PMID 30701815.

Zhang Y, Li W, Liu Z, Ye J, Zou G, Zhang Z. Combination therapy based on pegylated interferon alfa improves the therapeutic response of patients with chronic hepatitis B who exhibit high levels of hepatitis B e-antigen at 24 weeks: a retrospective observational study. Med (Baltim). 2019;98(36):e17022. doi: 10.1097/MD.0000000000017022. PMID 31490387.

Park EJ, Choi J, Lee KC, Na DH. Emerging pegylated non-biologic drugs. Expert Opin Emerg Drugs. 2019;24(2):107-19. doi: 10.1080/14728214.2019.1604684, PMID 30957581.

Hasselbalch HC, Holmstrom MO. Perspectives on interferon-alpha in the treatment of polycythemia vera and related myeloproliferative neoplasms: minimal residual disease and cure? Semin Immunopathol. 2019;41(1):5-19. doi: 10.1007/s00281-018-0700-2, PMID 30203226.

Ma P, Yang JM, Hou W, Song SD, Wang L, Lu W. A preliminary study on the efficacy and influencing factors of interferon for the treatment of genotype 1 chronic hepatitis C with different dosage forms. Eur J Gastroenterol Hepatol. 2013;25(5):601-5. doi: 10.1097/MEG.0b013e32835cc899, PMID 23263720.

Iftikhar U, Ahmed M, Saeed H, Saleem N, Bashir A, Farooq MS. Comparative safety and efficacy of conventional interferon versus pegylated-interferon based therapy for HCV: A retrospective cohort study from Gujranwala, Pakistan. Pak J Pharm Sci. 2020 Sep;33(5):2037-45. PMID 33824111.

Alsamman A, Othman M. Preparation and in vitro evaluation of fast release diazepam suppositories for febrile seizures. AJPCR. 2017;10(9):365-72. doi: 10.22159/ajpcr.2017.v10i9.20162.

Saeed AMH, Alaayedi MH, Alshohani ADH. New combination suppositories of lornoxicam and aloin for rheumatoid arthritis. Asian J Pharm Clin Res. 2018;11(2):308-12. doi: 10.22159/ajpcr.2018.v11i2.22921.

J Hasson K, G Jabar E, I Alkhalifa I. Evaluation of innovated formula of bisacodyl suppository following the dissolution profile and stability data using developed high-performance liquid chromatography method. Asian J Pharm Clin Res. 2020;13(1):5-10. doi: 10.22159/ajpcr.2020.v13i1.36222.

Azovtseva OV, Arhipov GS, Trofimova ТS. Pegylated interferon and ribavirin as an available variant of antiviral therapy for chronic hepatitis C in hiv infected. VIČ-infekc. immunosupr. 2017;9(3):39-46. doi: 10.22328/2077-9828-2017-9-3-39-46.

Miroshnikov PN, Lebedev LR. Development of the drug deltaferon based on an analogue of recombinant human gamma interferon. Bulletin of biotechnology and physico-chemical biology by Yu. Yu. A. Ovchinnikov. 2006;2(2):5-10.

Ershov FI, Kiselev OI. Interferons and their inducers: (from molecules to drugs). Moscow: Russian academy of medical Sciences: Geotar-medija; 2005.

Uchaikin V, Cherednichenko T, Malinovskaya V, Orlova T, Kovalev O, Kharlamova F. Use of recombinant alpha-2b-interferon in combination with antioxidants in the form of rectal suppositories (viferon) in children with chronic hepatitides B and C. Acta Virol. 2000 Apr;44(2):79-83. PMID 10989698.

Haruna Y, Inoue A. Minimal dose interferon suppository treatment suppresses viral replication with platelet counts and serum albumin levels increased in chronically hepatitis C virus-infected patients: a phase 1b, placebo-controlled, randomized study. J Interferon Cytokine Res. 2014;34(2):111-6. doi: 10.1089/jir.2013.0021, PMID 24070115.

Lipiainen T, Peltoniemi M, Sarkhel S, Yrjonen T, Vuorela H, Urtti A. Formulation and stability of cytokine therapeutics. J Pharm Sci. 2015;104(2):307-26. doi: 10.1002/jps.24243, PMID 25492409.

Abramovich RA, Bykov VA, Elagina IA, Papazova NA, Vorob’ev AN. Scientific approaches to development of medicinal formulation based on biotechnological substance. Antibiot Khimioter. 2012;57(1-2):13-6. PMID 22741196.

Experimental study of the acute toxicity of the oral form of pegylated interferon a2-b. SSMJ; 2018;(1). doi: 10.15372/SSMJ20180102.

Zhuk IE, Krivykh MA. Current issues of pharmaceutical development of interferon alfa-2b drugs. Clin Exp Pharmacol. 2018;81(5):83-4.

Korsun VN, Bruskin AB, Denisov LA, Ivanov RA. Comparative study of the pharmacokinetics of different dosage forms of interferon-alpha-2b. Effective pharmacotherapy. Obstet Gynecol. 2007;1:24-9.