Микрофлюидный метод как перспективная технология для синтеза антимикробных соединений

Цели. Цель исследования – проанализаровать применяющиеся антисептики и дезинфектанты, рассмотреть возможность синтеза различных антисептиков и отдельно синтеза олигогексаметиленгуанидина гидрохлорида (ОГМГ-ГХ) с применением микрофлюидной технологии, а также изучить основные параметры синтеза, влияющие на характеристики получаемого продукта.

Методы. Представлен обзор литературных источников, связанных с иследованиями антимикробной резистентности, применением средств на основе полигексаметиленгуанидина гидрохлорида, олигогексаметиленгуанидина гидрохлорида, а также других солей, полученных современными технологиями синтеза с использованием микрореакторов.

Результаты. Определена актуальность разработки технологии получения субстанции «ОГМГ–ГХ разветвленный». Рассмотрены существующие способы получения субстанции и их недостатки. Также рассмотрен микрофлюидный способ синтеза полимеров, его достоинства и перспективы его использования для получения целевой субстанции.

Выводы. Микрореакторные технологии позволяют более точно контролировать условия реакции поликонденсации исходных мономеров и повышать выход и селективность полученных олигомеров, что приводит к повышению чистоты продукта и эффективности процесса, в отличие от других известных способов. Использование микрореакторных технологий для синтеза разветвленных продуктов гидрохлорида олигогексаметиленгуанидина является перспективной стратегией.

1. Tsimmerman Ya.S. The problem of growing resistance of microorganisms to antibiotic therapy and prospects for Helicobacter pylori eradication. Klinicheskaya meditsina = Clinical Medicine (Russ. J.). 2013;91(6):14–20 (in Russ.).

2. Cabeen M.T., Jacobs-Wagner C. Bacterial cell shape. Nat. Rev. Microbiol. 2005;3(8):601–610. http://doi.org/10.1038/nrmicro1205

3. Silhavy T.J., Kahne D., Walker S. The bacterial cell envelope. Cold Spring Harb. Perspect. Biol. 2010;2:a000414. http://doi.org/10.1101/cshperspect.a000414

4. Russell A.D. Bacterial Spores and Chemical Sporicidal Agents. Clin. Microbial. Rev. Apr. 1990;3(2):99–119. https://doi.org/10.1128/CMR.3.2.99

5. Bowler P.G. Antibiotic resistance and biofilm tolerance: a combined threat in the treatment of chronic infections. J. Wound Care. 2018;27(5):273–277. https://doi.org/10.12968/jowc.2018.27.5.273

6. Stewart P.S., Franklin M.J. Physiological heterogeneity in biofilms. Nat. Rev. Microbiol. 2008;6(3):199–210. https://doi.org/10.1038/nrmicro1838

7. Kvashnina D.V., Kovalishena O.V. Prevalence of microbial resistance to chlorhexidine: a systematic review and analysis of regional monitoring. Fundamental’naya i klinicheskaya meditsina = Fundamental and Clinical Medicine. 2018;3(1):63–71 (in Russ.).

8. Akimkin V.G., Tutel’Yan A.V. Current directions of scientific researches in the field of infections, associated with the medical care, at the present stage. Zdorov’e naseleniya i sreda obitaniya – ZNiSO = Public Health and Life Environment – PH&LE. 2018;(4):46–50 (in Russ.).

9. Kultanova E.B., Turmukhambetova A.A., Kalieva D.K., Mukhamedzhan G.B. Nosocomial infections: a public health problem (literature review). Vestnik Kazakhskogo Natsional’nogo meditsinskogo universiteta (Vestnik KazNMU). 2018;(1):46–49 (in Russ.).

10. Exner M., et al. Antibiotic resistance: What is so special about multidrug-resistant Gram-negative bacteria? GMS Hyg. Infect. Control. 2017;12:Doc.05. http://doi.org/10.3205/dgkh000290

11. Privol’nev V.V., Zubareva N.A., Karakulina E.V. Topical therapy of wound infections: antiseptics or antibiotics? Klinicheskaya mikrobiologiya i antimikrobnaya khimioterapiya = Clinical Microbiology and Antimicrobial Chemotherapy. 2017;19(2):134–137 (in Russ.).

12. Tommasi R., Brown D.G., Walkup G.K., Manchester J.I., Miller A.A. ESKAPEing the labyrinth of antibacterial discovery. Nat. Rev. Drug Discov. 2015;14(8):529–542. https://doi.org/10.1038/nrd4572

13. Trombetta D., Saija A., Bisignano G., Arena S., Caruso S., Mazzanti G., Uccella N., Castelli F. Study on the Mechanisms of the Antibacterial Action of Some Plant α-βunsaturated Aldehydes. Letters in Applied Microbiology. 2002;35:285–290.

14. Bakhir V.M., Vtorenko V.I., Leonov B.I., et al. Efficiency and safety of chemical solutions for disinfection, presterilization cleaning and sterilization. Dezinfektsionnoe delo = Disinfection Affairs. 2003;(1):29–36 (in Russ.).

15. Larson E.L., Morton H.E. Alcohols. In: Block S.S. (Ed.). Disinfection, Sterilization, and Preservation. 4th Ed. Philadelphia, PA: Lea and Febiger; 1991, pp. 191–203.

16. Aronson J.K. (Ed.). Phenols. In: Meyler’s Side Effects of Drugs. 16th Ed. Elsevier; 2016, pp. 688–692. ISBN 9780444537164. https://doi.org/10.1016/B978-0-444-53717-1.01259-2

17. Lobanov S.M. Evaluation of effectiveness of chlorinecontaining disinfectant in case of disinfection of poultry farm objects. Problemy veterinarnoi sanitarii, gigieny i ekologii = Problems of Veterinary Sanitation, Hygiene and Ecology. 2011;2(6):49–51 (in Russ.).

18. Jumbelic M.I., Hanzlick R., Cohle S. Alkylamine antihistamine toxicity and review of Pediatric Toxicology Registry of the National Association of Medical Examiners. Report 4: Alkylamines. Am J Forensic Med Pathol. 1997 Mar;18(1):65–9. https://doi.org/10.1097/00000433-199703000-00012

19. Popov N.I., Volkovskii G.D., Michko S.A., Griganova N.V. Bianol test results. Veterinariya = Veterinary. 2005;(2):12–14 (in Russ.).

20. Khudyakov, A.A. Effective disinfection and selection of a disinfectant. Veterinariya = Veterinary. 2010;(2):18–22 (in Russ.).

21. Shestopalov N.V., Panteleeva L.G., Sokolova N.F., Abramova I.M., Lukichev S.P. Federal’nye klinicheskie rekomendatsii po vyboru khimicheskikh sredstv dezinfektsii i sterilizatsii dlya ispol’zovaniya v meditsinskikh organizatsiyakh (Federal clinical guidelines for the selection of disinfection and sterilization chemicals for use in medical organizations). Moscow: 2015. 67 р. (in Russ.). https://www.dezsnab-trade.ru/media/content/information/rekomendaciy_po_viboru_dezsredstv.pdf

22. Gotovskii D.G., Fomchenko I.V. Evaluation of the toxicity and biocidal properties of the disinfectant “Estadez with 3–2–1.” Uchenye zapiski UO VGAVM. 2012;48(1):18–22 (in Russ.).

23. Morozova N.S., Korzhenevskii S.V., Telenev A.V. The disinfection of microorganisms in the problem of nosocomial infections. Vestnik assotsiatsii. 2001;(3):15–17 (in Russ.).

24. Zhou Z., Wei D., Lu Y. Polyhexamethylene guanidine hydrochloride shows bactericidal advantages over chlorhexidine digluconate against ESKAPE bacteria. Biotechnol. Appl. Biochem. 2015;62(2):268–274. https://doi.org/10.1002/bab.1255

25. Lysytsya A., Mandygra M. The Antiviral Action of Polyhexamethylene Guanidine Derivatives. J. Life Sci. 2014;8(1):22–26.

26. Shandala M.G., Fedorova L.S., Pankratova G.P., Efimov K.M., Dityuk A.I., Snezhko A.G., Bogdanov A.I. Hygienic substantiation of the development and use of polyguanidines as antimicrobial prophylactic agents means of the innovative class. Gigiena i sanitariya = Hygiene and Sanitation. 2015;94(8):77–81 (in Russ.).

27. Belushkina N.N., Ivanov A.A., Krjukov L.N., Krjukova L.Ju., Moskaleva E.Ju., Pal’tsev M.A., Posypanova G.A., Severin E.S., Severin S.E., Torgun I.N., Fel’dman N.B., Khomjakov Ju.N. 2,2,6,6-tetrakis-(trifluoromethyl)-4ethylamino-5,6-dihydro-1,3,5-oxadiazine (synthazin), method of its synthesis and pharmaceutical composition based on thereof: Pat. 2203892 RF. Publ. 10.05.2003. (in Russ.).

28. Ivanov I.S., Shatalov D.O., Kedik S.A., Sedishev I.P., Beliakov S.V., Trachuk K.N., Komarova V.V. An effective method for preparation of high purity oligohexamethylene guanidine salts. Fine Chemical Technologies. 2020;15(3):31–38. https://doi.org/10.32362/2410-6593-2020-15-3-31-38

29. Vointseva I.I. Poliguanidiny – dezinfektsionnye sredstva i polifunktsional’nye dobavki v kompozitsionnye materialy (Polyguanidines are disinfectants and multifunctional additives in composite materials). Moscow: LKMpress; 2009. 303 p. (in Russ.). ISBN 978-5-9901286-2-0

30. Gembitskii P.A., Vointseva I.I. Polimernyi biotsidnyi preparat poligeksametilenguanidin (Polymer biocidal preparation polyhexamethylene guanidine). Zaporozh’e: Poligraf; 1998. 42 p. (in Russ.).

31. Arzamastsev A.P., Popkov V.A., Krasnyuk I.I., Matyushina G.P., Zadereiko L.V., Abrikosova Yu.A. Foaming composition for antiseptic treatment of the skin: Pat. 2003102506 RF. Publ. 10.08.2004. (in Russ.).

32. Moksunov V.V., Shestopalov N.V. Skin disinfection treatment agent: Pat. 2521323 RF. Publ. 27.06.2014. (in Russ.).

33. Kukharenko O., Bardeau J.F., Zaets I., Ovcharenko L., et al. Promising low cost antimicrobial composite material based on bacterial cellulose and polyhexamethylene guanidine hydrochloride. Eur. Polym. J. 2014;60:247–254. https://doi.org/10.1016/j.eurpolymj.2014.09.014

34. Wangkui W., Yin W. Pharmaceutical formula and preparation method of polyhexamethylene guanidine hydrochloride (PHMG): Pat. CN103705536A China. Publ. 09.04.2014.

35. Koffi-Nevry R., et al. Assessment of the antifungal activities of polyhexamethylene-guanidine hydrochloride (PHMGH)-based disinfectant against fungi isolated from papaya (Carica papaya L.) fruit. African J. Microbiol. Res. 2011;5(24):4162–4169.

36. Oulé M.K., Quinn K., Dickman M., Bernier A.M., Rondeau S., Moissac D.D., Boisvert A., Diop L. Akwaton, polyhexamethylene-guanidine hydrochloride-based sporicidal disinfectant: a novel tool to fight bacterial spores and nosocomial infections. J. Med. Microbiol. 2012;61(10):1421–1427. https://doi.org/10.1099/jmm.0.047514-0

37. Dilamian M., Montazer M., Masoumi J. Antimicrobial electrospun membranes of chitosan/poly(ethylene oxide) incorporating poly(hexamethylene biguanide) hydrochloride. Carbohydrate Polymers. 2013;94(1):364–371. https://doi.org/10.1016/j.carbpol.2013.01.059

38. Vitt A., Sofrata A., Slizen V., et al. Antimicrobial activity of polyhexamethylene guanidine phosphate in comparison to chlorhexidine using the quantitative suspension method. Ann. Clin. Microbiol. Antimicrob. 2015;14:36. https://doi.org/10.1186/s12941-015-0097-x

39. Vitt A., Gustafsson A., Ramberg P., Slizen V., Kazeko L. A., Buhlin K. Polyhexamethylene guanidine phosphate irrigation as anadjunctive to scaling and root planing in the treatment of chronic periodontitis. Acta Odontol. Scand. 2019;77(4):290–295. https://doi.org/10.1080/00016357.2018.1541099

40. Sklyanova Yu.A., Ushakov R.V., Kazimirskii V.A., et al. Experimental grounding of phogutsid (anavidin) application in stomatology. Byulleten’ Vostochno-Sibirskogo nauchnogo tsentra SO RAMN = Bul. VSNTS SB RAMS. 2006;4(50):344–346 (in Russ.).

41. Kha K.A., Grammatikova N.E., Vasilenko I.A., Kedik S.A. Comparative in vitro Antibacterial Activity of Polyhexamethylene Guanidine Hydrochloride and Polyhexamethylene Guanidine Succinate. Antibiotiki i khimioterapiya = Antibiotics and Chemotherapy. 2013;58(1–2):3–7 (in Russ.).

42. Guogang V. Polyhexamethylene guanidine medicine for treating stomach disease and preparation method and application thereof: Pat. CN105726491A China. Publ. 06.07.2016.

43. Khallyeva O.K., Dobysh V.A., Koktysh N.V., Belyasova N.A., Tarasevich V.A. Borne polyhexamethyleneguanidine salts. Uspekhi v khimii i khimicheskoi tekhnologii = Advances in Chemistry and Chemical Technology. 2016;30(1):11–13 (in Russ.).

44. Dobysh V.A., Koktysh N.V., Belyasova N.A., Kornei V.V. Study of structure and properties of the triple polymer-metal complex chitosan—Cu(II)—polyhexamethyleneguanidine. Izvestiya vuzov. Prikladnaya khimiya i biotekhnologiya = Proceedings of Universities. Applied Chemistry and Biotechnology. 2017;7(1):31–38 (in Russ.).

45. Ivanov I.S., Shatalov D.O., Kedik S.A., Sedishev I.P., Grammatikova N.E., Aidakova A.V., Trachuk K.N., Yazykova E.I. Study of the effect of the pharmaceutical substance branched oligohexamethylene guanidine hydrosuccinate in relation to microorganisms. Antibiotiki i khimioterapiya = Antibiotics and Chemotherapy. 2019;64(11–12):8–15 (in Russ.).

46. Kedik S.A., Sedishev I.P., Panov A.V., Zhavoronok E.S., Kha K.A. Guanidine derivative based branched oligomers and disinfectant containing said oligomers: Pat. RF 2443684C1. Publ. 27.02.2012. (in Russ.).

47. Safronov G.A., Gembitskii P.A., Kuznetsov O.Yu., Klyuev V.G., Kalinina T.A., Rodionov A.V. Method of producing disinfecting agent: Pat. SU-1616898 USSS. Publ. 30.12.1990.

48. Schmidt O. Method for producing polyhexamethylene guanidine: Pat. WO1999054291A1. Publ. 28.10.1991.

49. Popovkin V.V., Glukhov I.S., Antonov M.I. Method of producing polyhexamethylene guanidine hydrochloride: Pat. RF 2489452C1. Publ. 10.08.2013. (in Russ.).

50. Wei D., Ma Q., Guan Y., Hu F., Zheng A., Zhang X., Teng Z., Jiang H. Structural characterization and antibacterial activity of oligoguanidine (polyhexamethylene guanidine hydrochloride). Mat. Sci. Eng.: C. 2009;29(6):1776–1780. https://doi.org/10.1016/j.msec.2009.02.005

51. Terry S.C. A gas chromatography system fabricated on a silicon wafer using integrated circuit technology. PhD. Dissertation: Stanford University. ProQuest Dissertations Publishing; 1975.

52. Manz A., Graber N., Widmer H.M. Miniaturized total chemical analysis systems: A novel concept for chemical sensing. Sensors and Actuators B. 1990;1(1–6):244–248. https://doi.org/10.1016/0925-4005(90)80209-I

53. Srinivasan R., et al. Chemical performance and high temperature characterization of micromachined chemical reactors. In: Proceedings of International Solid State Sensors and Actuators Conference (Transducers 1997). 1997;1:163–166. https://doi.org/10.1109/SENSOR.1997.613608

54. Ehrfeld W., Golbig K., Hessel V., Löw, H. & Richter T. Characterization of mixing in micromixers by a test reaction: Single mixing units and mixer arrays. Ind. Eng. Chem. Res. 1999;38(3):1075–1082. https://doi.org/10.1021/ie980128d

55. Stone H.A., Stroock A.D., Ajdari A. Engineering flows in small devices. Microfluidics toward a lab-on-a chip. Annu. Rev. Fluid Mech. 2004;36(1):381–411. https://doi.org/10.1146/annurev.fluid.36.050802.122124

56. Reis M.H., Leibfarth F.A., Pitet LM. Polymerizations in Continuous Flow: Recent Advances in the Synthesis of Diverse Polymeric Materials. ACS Macro Lett. 2020;9(1):123−133. https://doi.org/10.1021/acsmacrolett.9b00933

57. Ivanov I.S., Kedik S.A., Shatalov D.O., et al. The Prospects of Application of Microfluidics for Synthesis of Compounds from the Alkylene Guanidine Series. Polym. Sci. Ser. D. 2021;14(2):305–311. https://doi.org/10.1134/S1995421221020088

58. Pihl J., Karlsson M., Chiu D.T. Microfluidic technologies in drug discovery. Drug Discov. Today. 2005;10(20):1377–1383. https://doi.org/10.1016/S13596446(05)03571-3

59. Schwalbe T., Autze V., Wille G. Chemical synthesis in microreactors. CHIMIA. Int. J. Chem. 2002;56(11):636–646. https://doi.org/10.2533/000942902777679984

60. Elvira K.S., Casadevall i Solvas X., Wootton R.C.R., DeMello A.J. The past, present and potential for microfluidic reactor technology in chemical synthesis. Nature chemistry. 2013;5:905–915. https://doi.org/10.1038/NCHEM.1753

61. Lee C-C., et al. Multistep synthesis of a radiolabeled imaging probe using integrated microfluidics. Science. 2005;310(5755):1793–1796. https://doi.org/10.1126/science.1118919

62. Asai T., et al. Switching reaction pathways of benzo[b] thiophen-3-yllithium and benzo[b]furan-3-yllithium based on high-resolution residence-time and temperature control in a flow microreactor. Chem. Lett. 2011;40(4):393–395. https://doi.org/10.1246/cl.2011.393

63. Illg T., Hessel V., Lob P., Schouten J.C. Continuous synthesis of tert-butyl peroxypivalate using a single-channel microreactor equipped with orifices as emulsification units. ChemSusChem. 2011;4(3):392–398. https://doi.org/10.1002/cssc.201000368

64. Vörös A., Baán Z., Mizsey P., Finta Z. Formation of Aromatic Amidoximes with Hydroxylamine using Microreactor Technology. Org. Proc. Res. Dev. 2012;16(11):1717−1726. https://doi.org/10.1021/op300113w

65. Zhang X., Stefanick S., Villani F.J. Application of Microreactor Technology in Process Development. Org. Proc. Res. Dev. 2004;8(3):455−460. https://doi.org/10.1021/op034193x

66. Marre S., Roïg Y., Aymonier C. Supercritical microfluidics: Opportunities in flow-through chemistry and materials science. J. Supercrit. Fluids. 2012;66:251–264. https://doi.org/10.1016/j.supflu.2011.11.029

67. Narkevich I.A., Tarasov I.N., Golant Z.M., Alekhin A.V. Modern technologies for the synthesis of pharmaceutical substances: way to high-efficiency drug production. Pharm. Chem. J. 2016;49(11):760–764. https://doi.org/10.1007/s11094-016-1366-5 [Original Russian Text: Narkevich I.A., Tarasov I.N., Golant Z.M., Alekhin A.V. Modern technologies for the synthesis of pharmaceutical substances: way to high-efficiency drug production. Khimiko-Farmatsevticheskii Zhurnal 2015;49(11):36–40. https://doi.org/10.30906/0023-1134-2015-49-11-36-40]

68. Bally F., Serra C. A., Brochon C., Hadziioannou G. Synthesis of Branched Polymers under ContinuousFlow Microprocess: An Improvement of the Control of Macromolecular Architectures. Macromol. Rapid Commun. 2011;32(22):1820−1825. https://doi.org/10.1002/marc.201100429

69. Visaveliya N., Köhler J.M. Role of Self-Polarization in a Single-Step Controlled Synthesis of Linear and Branched Polymer Nanoparticles. Macromol. Chem. Phys. 2015;216(11):1212−1219. https://doi.org/10.1002/macp.201500091

70. Kuesters C.F., Stengel B.F., Benzinger W., Brandner J.J. Microprocessing for preparing a polycondensate: Pat. US9187574B2 Publ. 17.11.2015.

71. Kockmann N., Gottsponer M., Zimmermann B., Roberge D.M. Enabling continuous-flow chemistry in microstructured devices for pharmaceutical and fine-chemical production. Chem. Eur. J. 2008;14(25):7470–7477. https://doi.org/10.1002/chem.200800707

72. Fletcher P., Haswell S. Downsizing synthesis. Chem. Brit. 1999;35(11):38–41.

73. Roberge D.M., Durcy L., Bieler N., Cretton P., Zimmermann B. Microreactor technology: A revolution for the fine chemical and pharmaceutical industries? Chem. Eng. Technol. 2005;28(3):318–322. https://doi.org/10.1002/ceat.200407128

74. Šalić A., Tušek A., Zelić, B. Application of microreactors in medicine and biomedicine. J. Appl. Biomed. 2012;10(3):137–153. https://doi.org/10.2478/v10136-012-0011-1

75. Wang Y., Chen Z., Bian F., Shang L., Zhu K., Zhao Y. Advances of droplet-based microfluidics in drug discovery. Expert Opin. Drug Discov. 2020;15(8):969–979. https://doi.org/10.1080/17460441.2020.1758663

76. Bogdan A.R., Poe S.L., Kubis D.C., Broadwater S.J., McQuade D.T. The Continuous‐Flow Synthesis of Ibuprofen. Angew. Chem. 2009;121(45):8699–8702. https://doi.org/10.1002/ange.200903055

77. Snead D.R., Jamison T.F. A three-minute synthesis and purification of ibuprofen: pushing the limits of continuousflow processing. Angew. Chem. 2014;54(3):983–987. https://doi.org/10.1002/anie.201409093

78. Pinho V.D., Gutmann B., Miranda L.S.M., de Souza R.O.M.A., Kappe C.O. Continuous Flow Synthesis of α-Halo Ketones: Essential Building Blocks of Antiretroviral Agents. J. Org. Chem. 2014;79(4):1555–1562. https://doi.org/10.1021/jo402849z

79. Poltavets Yu.I. Method for obtaining polymeric antitumor particles in flow microreactor and lyophilisate based on them: Pat. RF 2681933C1. Publ. 03.14.2019. (in Russ.).