Способы доставки линезолида к очагу туберкулезного воспаления: систематический обзор

Проанализированы 50 научных источников за период с 2018 по 2025 гг. о способах доставки лекарственных препаратов, а также преимуществах наночастиц линезолида. Противотуберкулезные препараты, принимаемые перорально, не всегда создают достаточную бактерицидную концентрацию в очаге поражения, независимо от их уровня в сыворотке крови. Вследствие этого даже при соблюдении режима лечения примерно у 1% пациентов может развиться туберкулез с множественной лекарственной устойчивостью (МЛУ-ТБ) из-за фармакокинетической вариабельности. Это определяет необходимость создания систем доставки, обеспечивающих таргетную подачу препарата непосредственно в пораженную легочную ткань. Для линезолида разработаны наноформы (сухие порошки, аэрозоли). Они стабильны до 6 месяцев и повышают биодоступность до 55,2%, что позволяет снизить дозу. Это открывает реальные перспективы для снижения терапевтических доз препарата.

1. Akinnawo C.A, Dube А. Clinically Relevant Metallic Nanoparticles in Tuberculosis Diagnosis and Therapy // Advanced Therapeutics. – 2024. – Vol. 8, № 4. – Р. 2400189.

2. An H., Deng X., Wang F., Xu P., Wang N. Dendrimers as Nanocarriers for the Delivery of Drugs Obtained from Natural Products // Polymers. – 2023. – Vol. 15, № 10. – Р. 2292. https://doi.org/10.3390/polym15102292

3. Bharti Sharma J., Bhatt S., Tiwari A., Tiwari V., Kumar M., Verma R., Kaushik D., Virmani T., Kumar G., Al Kamaly O., Saleh A., Khalid Parvez M., Alhalmi A. Statistical optimization of tetrahydrocurcumin loaded solid lipid nanoparticles using Box Behnken design in the management of streptozotocin-induced diabetes mellitus // Saudi pharmaceutical journal. – 2023. – Vol. 31, № 9. – Р. 101727. https://doi.org/10.1016/j.jsps.2023.101727

4. Borkar G., Chemate S. Formulation Development and Evaluation Studies of Linezolid Inhaler in the Treatment of Tuberculosis // International Journal of Pharmaceutical Sciences and Drug Research. – 2023. – Vol. 15, № 6. – Р. 722-729. https://doi.org/10.25004/IJPSDR.2023.150605

5. Burmistrova I.A. Vaniev E.V., Samoylova A.G., et al. The effectiveness of various approaches to the treatment of patients with isoniazid-resistant pulmonary tuberculosis // Tuberculosis and lung diseases. – 2023. – Vol. 101, № 5. – Р. 26-30.

6. Buya A.B., Witika B.A., Bapolisi A.M., Mwila C., Mukubwa G.K., Memvanga P.B., Makoni P.A., Nkanga C.I. Application of lipid-based nanocarriers for antitubercular drug delivery: a review // Pharmaceutics. – 2021. – Vol. 13, № 12. – Р. 2041. https://doi.org/10.3390/pharmaceutics13122041

7. Chikaura H., Nakashima Y., Fujiwara Y., Komohara Y., Takeya M., Nakanishi Y. Effect of particle size on biological response by human monocyte-derived macrophages // Biosurf Biotribol. – 2016. – Vol. 2, № 1. – Р. 18-25. https://doi.org/10.1016/j.bsbt.2016.02.003

8. Cirillo D.M., Miotto P., Tagliani E., ReSeqTB Consortium. Reaching consensus on drug resistance conferring mutations // International journal of mycobacteriology. – 2016. – Vol. 5, № 1. – Р. 33. https://doi.org/10.1016/j.ijmyco.2016.11.009

9. Colone M., Calcabrini A., Stringaro A. Drug Delivery Systems of Natural Products in Oncology // Molecules. – 2020. – Vol. 25, № 19. – Р. 4560. https://doi.org/10.3390/molecules25194560

10. Dallal Bashi Y.H., Mairs R., Murtadha R., Kett V. Pulmonary Delivery of Antibiotics to the Lungs: Current State and Future Prospects // Pharmaceutics. – 2025. – Vol. 17, № 1. – Р. 111.

11. Dua K., Hansbro P.M., Wadhwa R., Haghi M., Pont L.G., Williams K.A. Targeting chronic inflammatory lung diseases using advanced drug delivery systems. Academic Press, 2020. Available at: https://shop.elsevier.com/books/targeting-chronic-inflammatory-lung-diseases-using-advanced-drug-delivery-systems/dua/978-0-12-820658-4 [Accessed 27.09.2025].

12. French G. Safety and tolerability of linezolid // The Journal of antimicrobial chemotherapy. – 2003. – Vol. 51, Suppl 2. – Р. ii45-ii53. https://doi.org/10.1093/jac/dkg253

13. Garrabou G., Soriano A., López S., Guallar J.P., Giralt M., Villarroya F., Martínez J.A., Casademont J., Cardellach F., Mensa J., Miró Ò. Reversible Inhibition of Mitochondrial Protein Synthesis during Linezolid-Related Hyperlactatemia // Antimicrob Agents Chemother. – 2007. – Vol. 51, № 3. – Р. 962-967. https://doi.org/10.1128/aac.01190-06

14. Geiser M. Morphological aspects of particle uptake by lung phagocytes // Microscopy research and technique. – 2002. – Vol. 57, № 6. – Р. 512-522. https://doi.org/10.1002/jemt.10105

15. Global Tuberculosis Report 2024 / World Health Organization. – Geneva, 2024. – 68 p

16. Gomez A.I., Acosta M.F., Muralidharan P., et al. Advanced spray dried proliposomes of amphotericin B lung surfactant-mimic phospholipid microparticles/nanoparticles as dry powder inhalers for targeted pulmonary drug delivery // Pulmonary pharmacology & therapeutics. – 2020. – № 64. – Р. 101975. https://doi.org/10.1016/j.pupt.2020.101975

17. Goswami R. The Role of Metallic Nanoparticles in Inhibition of Mycobacterium Tuberculosis and Enhances Phagosome Maturation into the Infected Macrophage // Oman Medical Journal. – 2020 – Vol. 35, № 6. – Р. 194. https://doi.org/10.5001/OMJ.2020.78

18. Imperial M.Z., Nedelman J.R., Conradie F., Savic R.M. Proposed Linezolid Dosing Strategies to Minimize Adverse Events for Treatment of Extensively Drug-Resistant Tuberculosis // Clinical infectious diseases. – 2022. – Vol. 74, № 10. – Р. 1736-1747. https://doi.org/10.1093/cid/ciab699

19. Isles M.P. Nanomedicines and Nanosimilars-Why a Robust Centralised Regulatory Framework Is Essential to Enhance Patient Safety // Frontiers in pharmacology. – 2022. – № 12. – Р. 787239. https://doi.org/10.3389/fphar.2021.787239

20. Kamble R.N. Development and Characterization of Linezolid loaded Biocompatible Solid-lipid based Nanocarrier for Enhanced Lung Deposition and Anti-tubercular Activity tailor-made Carrier for Dry Powder Inhaler //Current Indian Science. – 2023. – Vol. 1. – №. 1. – Р. E080523216630.

21. Kempker R.R., Heinrichs M.T., Nikolaishvili K., Sabulua I., Bablishvili N., Gogishvili S., Avaliani Z., Little B.P., Bernheim A., Derendorf H., Blumberg H.M., Vashakidze S., Peloquin C.A. A comparison of linezolid lung tissue concentrations among patients with drug-resistant tuberculosis // The European respiratory journal. – 2018. – Vol. 51, № 2. – Р. 1702166.

22. Kesharwani P. (ed.) Nanotechnology based approaches for tuberculosis treatment. – Academic Press, 2020. Available at: https://shop.elsevier.com/books/nanotechnology-based-approachesfor-tuberculosis-treatment/kesharwani/978-0-12-819811-7 [Accessed 27.09.2025].

23. Kumar G., Virmani T., Pathak K., Kamaly O.A., Saleh A. Central Composite Design Implemented Azilsartan Medoxomil Loaded Nanoemulsion to Improve Its Aqueous Solubility and Intestinal Permeability: In Vitro and Ex Vivo Evaluation // Pharmaceuticals (Basel). – 2022. – Vol. 15. № 11. – Р. 1343. https://doi.org/10.3390/ph15111343

24. Kumar G., Virmani T., Sharma A., Pathak K. Codelivery of phytochemicals with conventional anticancer drugs in form of nanocarriers // Pharmaceutics. – 2023. – Vol. 15, № 3. – Р. 889. https://doi.org/10.3390/pharmaceutics15030889

25. Makled S., Boraie N., Nafee N. Nanoparticle-mediated macrophage targeting-a new inhalation therapy tackling tuberculosis // Drug Deliv Transl Res. – 2021. – Vol. 11, № 3. – Р.1037-1055. https://doi.org/10.1007/s13346-020-00815-3

26. Mater J., Chem B. Size-dependent antimycobacterial activity of titanium oxide nanoparticles against Mycobacterium tuberculosis // Journal of Materials Chemistry B. – 2019. – № 7. – Р. 4338-4346. https://doi.org/10.1039/C9TB00784A

27. Meravanige G., Thippeswamy M., Shiroorkar P., et al. Chitosan-Based Linezolid Dry Powder Inhalers: A Novel Approach for Targeted Pulmonary Delivery in Tuberculosis Treatment // Indian Journal of Pharmaceutical Education and Research. – 2025. – Vol. 59. – № 1s. – P. s138-s150.

28. Muravyeva A.I., Zavarzina V.V., Gukasova N.V., Kuznetsov S.L., Tubasheva I.A., Vorontsov E.A. Complex polymer compositions based on antibiotics linezolid, rifabutin, prothionamide // Issues of biological, medical and pharmaceutical chemistry. – 2018 – Vol. 21, № 5. – Р. 27-33.

29. Nabi B., Rehman S., Aggarwal S., Baboota S., Ali J. Nano-based anti-tubercular drug delivery: an emerging paradigm for improved therapeutic intervention // Drug delivery and translational research. – 2020. – Vol. 10, № 4. – Р. 1111-1121. https://doi.org/10.1007/s13346-020-00786-5

30. Park H., Otte A., Park K. Evolution of drug delivery systems: From 1950 to 2020 and beyond // Journal of controlled release: official journal of the Controlled Release Society. – 2022. – № 342. – Р. 53-65. https://doi.org/10.1016/j.jconrel.2021.12.030

31. Pham D.D., Fattal E., Tsapis N. Pulmonary drug delivery systems for tuberculosis treatment // International journal of pharmaceutics. – 2015. – Vol. 478, № 2. – Р. 517-529. https://doi.org/10.1016/j.ijpharm.2014.12.009

32. Rani S., Sharma A.K., Kasu R., Gupta U. Polymeric Nanoparticles: A Holistic Approach to Combat Tuberculosis // Critical reviews in therapeutic drug carrier systems. – 2022. – Vol. 39, № 5. – Р. 83-115. https://doi.org/10.1615/CritRevTherDrugCarrierSyst.2022039981

33. Shah S., Maheshwari H., Soniwala M., et al. Pulmonary delivery 44of linezolid nanoparticles for treatment of tuberculosis: design, development, and optimization //Journal of Pharmaceutical Innovation. – 2022. – Vol. 17. – № 1. – Р. 46-59.

34. Shah S., Cristopher D., Sharma S., et al. Inhalable linezolid loaded PLGA nanoparticles for treatment of tuberculosis: design, development and in vitro evaluation //Journal of Drug Delivery Science and Technology. – 2020. – № 60. – P. 102013.

35. Sharma Y., Mahar R., Chakraborty A., Nainwal N. Optimizing the formulation variables for encapsulation of linezolid into polycaprolactone inhalable microspheres using double emulsion solvent evaporation //Tuberculosis. – 2023. – № 143. – Р. 102417.

36. Sheikhpour M., Delorme V., Kasaeian A., Amiri V., Masoumi M., Sadeghinia M., Ebrahimzadeh N., Maleki M., Pourazar S. An effective nano drug delivery and combination therapy for the treatment of Tuberculosis // Scientific reports. – 2022. – Vol. 12, № 1. – Р. 9591. https://doi.org/10.1038/s41598-022-13682-4

37. Singh S., Virmani T., Kohli K. Nanoemulsion system for improvement of raspberry ketone oral bioavailability // Indo Global Journal of Pharmaceutical Sciences. – 2020. – Vol. 10, № 01. – Р. 33-42. https://doi.org/10.35652/IGJPS.2020.10105

38. Srivastava S., Pasipanodya J.G., Meek C., Leff R., Gumbo T. Multidrug-resistant tuberculosis not due to noncompliance but to between-patient pharmacokinetic variability // The Journal of infectious diseases. – 2011. – Vol. 204, 12. – Р. 1951-1959. https://doi.org/10.1093/infdis/jir658

39. Thwaites G., Nguyen N.V. Linezolid for Drug-Resistant Tuberculosis // The New England journal of medicine. – 2022. – Vol. 387, № 9. – Р. 842-843. https://doi.org/10.1056/NEJMe2208554

40. Tiddens H.A., Bos A.C., Mouton J.W., Devadason S., Janssens H.M. Inhaled antibiotics: dry or wet? // The European respiratory journal. – 2014. – Vol. 44, № 5. – Р. 1308-1318. https://doi.org/10.1183/09031936.00090314

41. van Rensburg L., van Zyl J.M., Smith J. Deposition and transport of linezolid mediated by a synthetic surfactant Synsurf® within a pressurized metered dose inhaler: a Calu-3 model // Drug Des Devel Ther. – 2018. – № 12. – Р. 1107-1118. https://doi.org/10.2147/DDDT.S147035

42. Vasilyeva I.A., Sterlikov S.A., Testov V.V., et al. Sectoral and economic indicators of anti-tuberculosis work in 2022–2023: statistical materials» - M.: FGBU «NMIC FPI» MINZDRAVA ROSSII, 2024. – 59 р.

43. Verbeeck R.K., Günther G., Kibuule D., Hunter C., Rennie T.W. Optimizing treatment outcome of first-line anti-tuberculosis drugs: the role of therapeutic drug monitoring // European journal of clinical pharmacology. – 2016. – Vol. 72, № 8. – Р. 905-916. https://doi.org/10.1007/s00228-016-2083-4

44. Virmani T., Kumar G., Virmani R., Sharma A., Pathak K. Nanocarrier-based approaches to combat chronic obstructive pulmonary disease // Nanomedicine (London, England). – 2022. – Vol. 17, № 24. – Р. 1833-1854. https://doi.org/10.2217/nnm-2021-0403

45. Virmani, T., Kumar, G., Sharma, A., Pathak, K., Akhtar, M. S., Afzal, O., & Altamimi, A.S.A. Amelioration of Cancer Employing Chitosan, Its Derivatives, and Chitosan-Based Nanoparticles: Recent Updates // Polymers. – 2023. – Vol. 15, № 13. – Р. 2928. https://doi.org/10.3390/polym15132928

46. Warsi M.H., Mohapatra S., Asfer M., Yusuf M., Ali A., Rahman M.A., Ali A., Qadir A., Jain G.K. Development and Antibacterial Investigation of Linezolid-Loaded SPIONs and HPLC Method Development for Quantitative Analysis of Linezolid // J AOAC Int. – 2023. – Vol. 106. № 5. – Р. 1180-1189. https://doi.org/10.1093/jaoacint/qsad071

47. Wenzler E., Fraidenburg D.R., Scardina T., Danziger L.H. Inhaled Antibiotics for Gram-Negative Respiratory Infections // Clinical microbiology reviews. – 2016 – Vol. 29, № 3. – Р. 581-632. https://doi.org/10.1128/CMR.00101-15

48. WHO consolidated guidelines on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment, 2022 update. Geneva, World Health Organization, 2022, 150 p.

49. Zhang P., Li W., Liu M., Zhan S., Zhang H., Deng G., Chen X. Linezolid-Associated Neuropathy in Patients with MDR/XDR Tuberculosis in Shenzhen, China // Infect Drug Resist. – 2022. – № 15. – Р. 2617-2624. https://doi.org/10.2147/IDR.S365371

50. Zomorodbakhsh S., Abbasian Y., Naghinejad M., Sheikhpour M. The Effects Study of Isoniazid Conjugated Multi-Wall Carbon Nanotubes Nanofluid on Mycobacterium tuberculosis // International journal of nanomedicine. – 2020. – № 15. – Р. 5901-5909. https://doi.org/10.2147/IJN.S251524