Интраназальное введение как способ доставки лекарств в головной мозг (обзор)

Введение. Интраназальная доставка лекарственных средств напрямую из носа в мозг является одним из многообещающих направлений для лечения заболеваний головного мозга, включающих нейродегенеративные расстройства, инсульт, опухоли головного мозга и т. д.

Текст. Доставка лекарства через нос имеет ряд преимуществ, среди которых быстрое наступление фармакологического эффекта, возможность обхода гематоэнцефалического барьера, снижение вероятности возникновения побочных эффектов, а также быстрый и неинвазивный способ введения. Однако существенными недостатками данного пути является сравнительно быстрое вымывание с поверхности слизистой оболочки, плохое проникновение лекарства через слизистую носа, мукоцилиарный клиренс и действие протеолитических ферментов. В настоящее время для преодоления вышеуказанных ограничений используются различные направления, среди которых следует отметить разработку систем доставки из носа в мозг, представляющих собой мукоадгезивные, мукус-проникающие и гелеобразующие системы, способствующие удерживанию или проникновению лекарств через слизистую оболочку. При этом значительную роль при конструировании такого рода систем занимают высокомолекулярные соединения. В частности, мукоадгезивные системы могут быть получены из катионных и анионных полимеров. Недавние исследования также показали проявление мукоадгезивных свойств у интерполиэлектролитных комплексов. Увеличение мукоадгезивных свойств полимеров при конструировании систем доставки лекарств может быть также достигнуто путем присоединения к ним различных функциональных групп, таких как тиолы, малеимиды, акрилаты, метакрилаты, катехолы и т. д. Мукус-проникающие системы могут быть получены путем ПЭГилирования наночастиц, а также функционализацией с помощью некоторых поли-(2-оксазолинов), поливинилового спирта и др., что было показано на других слизистых оболочках организма. Наконец, увеличение проникновения возможно достичь путем использования муколитических средств в комбинации с неионогенными поверхностно-активными веществами. Другим подходом для увеличения эффективности доставки лекарств из носа в мозг является использование гелеобразующих систем. В частности, актуальным является гелеобразование in situ. Данный вид гелей на первом этапе представляет собой раствор, в дальнейшем в ответ на химическое и физическое воздействие происходит фазовый переход, сопровождающийся образованием геля. В зависимости от внешней стимуляции фазового перехода различают термо-, рН-, ионообратимые и другие системы, показавшие свою эффективность для доставки в мозг путем интраназального введения.

Заключение. Эффективная интраназальная доставка лекарственных средств и терапевтических агентов в мозг может быть достигнута путем использования мукоадгезивных, мукус-проникающих и гелеобразующих систем и/или их комбинаций.

1. Crowe T. P., Greenlee M. H. W., Kanthasamy A. G., Hsu W. H. Mecha-nism of intranasal drug delivery directly to the brain. Life Sciences. 2018;195:44–52. DOI: 10.1016/j.lfs.2017.12.025.

2. Brown R. C., Lockwood A. H., Sonawane B. R. Neurodegenerative Diseases: An Overview of Environmental Risk Factors. Environmental Health Perspectives. 2005;113(9):1250–1256. DOI: 10.1289/ehp.7567.

3. Patel A., Surti N., Mahajan A. Intranasal drug delivery: Novel delivery route for effective management of neurological disorders. Journal of Drug Delivery Science and Technology. 2019;52:130–137. DOI: 10.1016/j.jddst.2019.04.017.

4. Nguyen T. T., Nguyen T. T. D., Nguyen T. K. O., Vo T. K., Vo V. G. Advances in developing therapeutic strategies for Alzheimer’s disease. Biomedicine & Pharmacotherapy. 2021;139:111623. DOI: 10.1016/j.biopha.2021.111623.

5. Tolosa E., Garrido A., Scholz S.W., Poewe W. Challenges in the diagnosis of Parkinson’s disease. The Lancet Neurology. 2021;20(5):385–397. DOI: 10.1016/S1474-4422(21)00030-2.

6. Wright G. E. B., Black H. F., Collins J. A., Gall-Duncan T., Caron N. S., Pearson C. E., Hayden M. R. Interrupting sequence variants and age of onset in Huntington's disease: clinical implications and emerging therapies. The Lancet Neurology. 2020;19(11):930–939. DOI: 10.1016/S1474-4422(20)30343-4.

7. Schuchman E. H., Desnick R. J. Types A and B Niemann-Pick disease. Molecular Genetics and Metabolism. 2017;120(1–2):27–33. DOI: 10.1016/j.ymgme.2016.12.008.

8. Deramecourt V., Slade J. Y., Oakley A. E., Perry R. H., Ince P. G., Maurage C.-A., Kalaria R. N. Staging and natural history of cerebrovascular pathology in dementia. Neurology. 2012;78(14):1043–1050. DOI: 10.1212/WNL.0b013e31824e8e7f.

9. O’Brien J. T., Erkinjuntti T., Reisberg B., Roman G., Sawada T., Pantoni L., Bowler J. V., Ballard C., DeCarli C., Gorelick P. B., Rockwood K., Burns A., Gauthier S., DeKosky S. T. Vascular cognitive impairment. The Lancet Neurology. 2003;2(2):89-98. DOI: 10.1016/S1474-4422(03)00305-3.

10. Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. The Lancet Neurology. 2010;9(7):689–701. DOI: 10.1016/S1474-4422(10)70104-6.

11. Charidimou A., Pantoni L., Love S. The concept of sporadic cerebral small vessel disease: A road map on key definitions and current concepts. International Journal of Stroke. 2016;11(1):6–18. DOI: 10.1177/1747493015607485.

12. Wardlaw J. M., Smith C., Dichgans M. Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. The Lancet Neurology. 2013;12(5):483–497. DOI: 10.1016/S1474-4422(13)70060-7.

13. Seyfried T. N., Kiebish M. A., Marsh J., Shelton L. M., Huysentruyt L. C., Mukherjee P. Metabolic management of brain cancer. Biochimica et Biophysica Acta (BBA) – Bioenergetics. 2011;1807(6):577–594. DOI: 10.1016/j.bbabio.2010.08.009.

14. Han L., Jiang C. Evolution of blood–brain barrier in brain diseases and related systemic nanoscale brain-targeting drug delivery strategies. Acta Pharmaceutica Sinica B. 2021;11(8):2306–2325. DOI: 10.1016/j.apsb.2020.11.023.

15. Abbott N. J., Patabendige A. A. K., Dolman D. E. M., Yusof S. R., Begley D. J. Structure and function of the blood–brain barrier. Neurobiology of Disease. 2010;37(1):13–25. DOI: 10.1016/j.nbd.2009.07.030.

16. Lee C. S., Leong K.W. Advances in microphysiological blood-brain barrier (BBB) models towards drug delivery. Current Opinion in Biotechnology. 2020;66:78–87. DOI: 10.1016/j.copbio.2020.06.009.

17. Sharma G., Sharma A. R., Lee S.-S., Bhattacharya M., Nam J-.S., Chakraborty C. Advances in nanocarriers enabled brain targeted drug delivery across blood brain barrier. International Journal of Pharmaceutics. 2019;559:360–372. DOI: 10.1016/j.ijpharm.2019.01.056

18. Costa C. P., Moreira J. N., Sousa Lobo J. M., Silva A. C. Intranasal delivery of nanostructured lipid carriers, solid lipid nanoparticles and nanoemulsions: A current overview of in vivo studies. Acta Pharmaceutica Sinica B. 2021;11(4):925–940. DOI: 10.1016/j.apsb.2021.02.012.

19. Lochhead J. J., Thorne R. G. Intranasal delivery of biologics to the central nervous system. Advanced Drug Delivery Reviews. 2012;64(7):614–628. DOI: 10.1016/j.addr.2011.11.002.

20. Misra A., Kher G. Drug Delivery Systems from Nose to Brain. Current Pharmaceutical Biotechnology. 2012;13(12):2355–2379. DOI: 10.2174/138920112803341752.

21. Costa C., Moreira J. N., Amaral M. H., Sousa Lobo J. M., Silva A. C. Nose-to-brain delivery of lipid-based nanosystems for epileptic seizures and anxiety crisis. Journal of Controlled Release. 2019;295:187–200. DOI: 10.1016/j.jconrel.2018.12.049.

22. Arora P., Sharma S., Garg S. Permeability issues in nasal drug delivery. Drug Discovery Today. 2002;7(18):967–975. DOI: 10.1016/S1359-6446(02)02452-2.

23. Grassin-Delyle S., Buenestado A., Naline E., Faisy C., Blouquit-Laye S., Couderc L.-J., Le Guen M., Fischler M., Devillier P. Intranasal drug delivery: An efficient and non-invasive route for systemic administration. Pharmacology & Therapeutics. 2012;134(3):366–379. DOI: 10.1016/j.pharmthera.2012.03.003.

24. Watelet J. B., Van Cauwenberge P. Applied anatomy and physiology of the nose and paranasal sinuses. Allergy. 1999;54(s57):14–25. DOI: 10.1111/j.1398-9995.1999.tb04402.x.

25. Erdő F., Bors L.A., Farkas D., Bajza Á., Gizurarson S. Evaluation of intranasal delivery route of drug administration for brain targeting. Brain Research Bulletin. 2018;143:155–170. DOI: 10.1016/j.brainresbull.2018.10.009.

26. Mittal D., Ali A., Md S., Baboota S., Sahni J. K., Ali J. Insights into direct nose to brain delivery: current status and future perspective. Drug Delivery. 2014;21(2):75–86. DOI: 10.3109/10717544.2013.838713.

27. Gänger S., Schindowski K. Tailoring Formulations for Intranasal Nose-to-Brain Delivery: A Review on Architecture, Physico-Chemical Characteristics and Mucociliary Clearance of the Nasal Olfactory Mucosa. Pharmaceutics. 2018;10(3):116. DOI: 10.3390/pharmaceutics10030116.

28. Bourganis V., Kammona O., Alexopoulos A., Kiparissides C. Recent advances in carrier mediated nose-to-brain delivery of pharmaceutics. European Journal of Pharmaceutics and Biopharmaceutics. 2018;128:337–362. DOI: 10.1016/j.ejpb.2018.05.009.

29. Ugwoke M. I., Verbeke N., Kinget R. The biopharmaceutical aspects of nasal mucoadhesive drug delivery. Journal of Pharmacy and Pharmacology. 2001;53(1):3–21. DOI: 10.1211/0022357011775145.

30. Dhuria S. V., Hanson L. R., Frey W. H . Intranasal delivery to the central nervous system: Mechanisms and experimental considerations. Journal of Pharmaceutical Sciences. 2010;99(4):1654–1673. DOI: 10.1002/jps.21924.

31. Inoue D., Tanaka A., Kimura S., Kiriyama A., Katsumi H., Yamamoto A., Ogawara K-I., Kimura T., Higaki K., Yutani R., Sakane T., Furubayashi T. The relationship between in vivo nasal drug clearance and in vitro nasal mucociliary clearance: Application to the prediction of nasal drug absorption. European Journal of Pharmaceutical Sciences. 2018;117:21–26. DOI: 10.1016/j.ejps.2018.01.032.

32. Mall M. A. Role of Cilia, Mucus, and Airway Surface Liquid in Mucociliary Dysfunction: Lessons from Mouse Models. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2008;21(1):13–24. DOI: 10.1089/jamp.2007.0659.

33. Lansley A. B. Mucociliary clearance and drug delivery via the respiratory tract. Advanced Drug Delivery Reviews. 1993;11:299–327. DOI: 10.1016/0169-409X(93)90014-U.

34. Braiman A., Priel Z. Efficient mucociliary transport relies on efficient regulation of ciliary beating. Respiratory Physiology & Neurobiology. 2008;163(1–3):202–207. DOI: 10.1016/j.resp.2008.05.010.

35. Alsarra I. A., Hamed A. Y., Alanazi F. K., El Maghraby G. M. Vesicular Systems for Intranasal Drug Delivery. In: Drug Delivery to the Central Nervous System. Totowa: Humana Press; 2009. P. 175–203. DOI: 10.1007/978-1-60761-529-3_8.

36. Zarshenas M. M., Zargaran A., Müller J., Mohagheghzadeh A. Nasal Drug Delivery in Traditional Persian Medicine. Jundishapur Journal of Natural Pharmaceutical Products. 2013;8(3):144–148. DOI: 10.17795/jjnpp-9990.

37. Chan A. S., Cheung M., Sze S. L., Leung W. W., Shi D. An Herbal Nasal Drop Enhanced Frontal and Anterior Cingulate Cortex Activity. Evidence-Based Complementary and Alternative Medicine. 2011;2011:543648–543656. DOI: 10.1093/ecam/nep198.

38. Al-Ghananeem A. M., Traboulsi A. A., Dittert L. W., Hussain A. A. Targeted brain delivery of 17β-estradiol via nasally administered water soluble prodrugs. AAPS PharmSciTech. 2002;3(1):40–47. DOI: 10.1208/pt030105.

39. Kao H. D., Traboulsi A., Itoh S., Dittert L., Hussain A. Enhancement of the systemic and CNS specific delivery of L-dopa by the nasal administration of its water soluble prodrugs. Pharmaceutical Research. 2000;17(8):978–984. DOI: 10.1023/A:1007583422634.

40. Serralheiro A., Alves G., Fortuna A., Falcão A. Intranasal administration of carbamazepine to mice: A direct delivery pathway for brain targeting. European Journal of Pharmaceutical Sciences. 2014;60:32–39. DOI: 10.1016/j.ejps.2014.04.019.

41. Sin B., Wiafe J., Ciaramella C., Valdez L., Motov S. M. The use of intranasal analgesia for acute pain control in the emergency department: A literature review. The American Journal of Emergency Medicine. 2018;36(2):310–318. DOI: 10.1016/j.ajem.2017.11.043.

42. Agrawal M., Saraf S., Saraf S., Antimisiaris S. G., Chougule M. B., Shoyele S. A., Alexander A. Nose-to-brain drug delivery: An update on clinical challenges and progress towards approval of anti-Alzheimer drugs. Journal of Controlled Release. 2018;281:139– 177. DOI: 10.1016/j.jconrel.2018.05.011.

43. Costantino H. R., Illum L., Brandt G., Johnson P. H., Quay S. C. Intranasal delivery: Physicochemical and therapeutic aspects. International Journal of Pharmaceutics. 2007;337(1–2):1–24. DOI: 10.1016/j.ijpharm.2007.03.025.

44. Keech B., Crowe S., Hocking D. R. Intranasal oxytocin, social cognition and neurodevelopmental disorders: A meta-analysis. Psychoneuroendocrinology. 2018;87:9–19. DOI: 10.1016/j.psyneuen.2017.09.022.

45. Oppong-Damoah A., Zaman R. U., D’Souza M. J., Murnane K. S. Nanoparticle encapsulation increases the brain penetrance and duration of action of intranasal oxytocin. Hormones and Behavior. 2019;108:20–29. DOI: 10.1016/j.yhbeh.2018.12.011.

46. Ozsoy Y., Gungor S., Cevher E. Nasal Delivery of High Molecular Weight Drugs. Molecules. 2009;14(9):3754–3779. DOI: 10.3390/molecules14093754.

47. Rhea E. M., Salameh T. S., Banks W. A. Routes for the delivery of insulin to the central nervous system: A comparative review. Experimental Neurology. 2019;313:10–15. DOI: 10.1016/j.expneurol.2018.11.007.

48. Craft S. Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment. Archives of Neurology. 2012;69(1):29–38. DOI: 10.1001/archneurol.2011.233.

49. Simon K. U., Neto E. W., dos Santos Tramontin N., Canteiro P. B., da Costa Pereira B., Zaccaron R. P., Silveira P. C. L., Muller A. P. Intranasal insulin treatment modulates the neurotropic, inflammatory, and oxidant mechanisms in the cortex and hippocampus in a low-grade inflammation model. Peptides. 2020;123:170175. DOI: 10.1016/j.peptides.2019.170175.

50. Salameh T. S., Bullock K. M., Hujoel I. A., Niehoff M. L., Wolden-Hanson T., Kim J., Morley J. E., Farr S. A., Banks W. A. Central Nervous System Delivery of Intranasal Insulin: Mechanisms of Uptake and Effects on Cognition. Journal of Alzheimer’s Disease. 2015;47(3):715–728. DOI: 10.3233/JAD-150307.

51. Yu H., Kim K. Direct nose-to-brain transfer of a growth hormone releasing neuropeptide, hexarelin after intranasal administration to rabbits. International Journal of Pharmaceutics. 2009;378(1–2):73–79. DOI: 10.1016/j.ijpharm.2009.05.057.

52. Ren Z., Zhao Y., Liu J., Ji X., Meng L., Wang T., Sun W., Zhang K., Sang X., Yu Z., Li Y., Feng N., Wang H., Yang D., Yang Z., Ma Y., Gao Y., Xia X. Intramuscular and intranasal immunization with an H7N9 influenza viruslike particle vaccine protects mice against lethal influenza virus challenge. International Immunopharmacology. 2018;58:109–116. DOI: 10.1016/j.intimp.2017.12.020.

53. Bahadur S., Pathak K. Physicochemical and physiological conside-rations for efficient nose-to-brain targeting. Expert Opinion on Drug Delivery. 2012;9(1):19–31. DOI: 10.1517/17425247.2012.636801.

54. Pires A., Fortuna A., Alves G., Falcão A. Intranasal Drug Delivery: How, Why and What for? Journal of Pharmacy & Pharmaceutical Sciences. 2009;12(3):288–311. DOI: 10.18433/J3NC79.

55. Tian B., Liu Y., Liu J. Chitosan-based nanoscale and non-nanoscale delivery systems for anticancer drugs: A review. European Polymer Journal. 2021;154:110533. DOI: 10.1016/j.eurpolymj.2021.110533.

56. Pacheco C., Sousa F., Sarmento B. Chitosan-based nanomedicine for brain delivery: Where are we heading? Reactive and Functional Polymers. 2020;146:104430. DOI: 10.1016/j.reactfunctpolym.2019.104430.

57. García-González C. A., Uy J. J., Alnaief M., Smirnova I. Preparation of tailor-made starch-based aerogel microspheres by the emulsion-gelation method. Carbohydrate Polymers. 2012;88(4):1378–1386. DOI: 10.1016/j.carbpol.2012.02.023.

58. Kundu D., Banerjee T. Development of microcrystalline cellulose based hydrogels for the in vitro delivery of Cephalexin. Heliyon. 2020;6(1):e03027. DOI: 10.1016/j.heliyon.2019.e03027.

59. Vasvani S., Kulkarni P., Rawtani D. Hyaluronic acid: A review on its biology, aspects of drug delivery, route of administrations and a special emphasis on its approved marketed products and recent clinical studies. International Journal of Biological Macromolecules. 2020;151:1012–1029. DOI: 10.1016/j.ijbiomac.2019.11.066.

60. Varshosaz J. Dextran conjugates in drug delivery. Expert Opinion on Drug Delivery. 2012;9(5):509–523. DOI: 10.1517/17425247.2012.673580.

61. Lei C., Liu X.-R., Chen Q.-B., Li Y., Zhou J.-L., Zhou L.-Y., Zou T. Hyaluronic acid and albumin based nanoparticles for drug delivery. Journal of Controlled Release. 2021;331:416-433. DOI: 10.1016/j.jconrel.2021.01.033.

62. Jahanban-Esfahlan R., Derakhshankhah H., Haghshenas B., Mas-soumi B., Abbasian M., Jaymand M. A bioinspired magnetic natural hydrogel containing gelatin and alginate as a drug delivery system for cancer chemotherapy. International Journal of Biological Macromolecules. 2020;156:438–445. DOI: 10.1016/j.ijbiomac.2020.04.074.

63. Liu S., Qin S., He M., Zhou D., Qin Q., Wang H. Current applications of poly(lactic acid) composites in tissue engineering and drug delivery. Composites Part B: Engineering. 2020;199:108238. DOI: 10.1016/j.compositesb.2020.108238.

64. Kipper M. J., Shen E., Determan A., Narasimhan B. Design of an injectable system based on bioerodible polyanhydride microspheres for sustained drug delivery. Biomaterials. 2002;23(22):4405–4412. DOI: 10.1016/S0142-9612(02)00181-3.

65. Porfiryeva N. N., Moustafine R. I., Khutoryanskiy V. V. PEGylated Systems in Pharmaceutics. Polymer Science, Series C. 2020;61:62–74. DOI: 10.1134/S181123822001004X.

66. Wei X., Gong C., Gou M., Fu S., Guo Q., Shi S., Luo F., Guo G., Qiu L., Qian Z. Biodegradable poly(ε-caprolactone)–poly(ethylene glycol) copolymers as drug delivery system. International Journal of Pharmaceutics. 2009;381(1):1–18. DOI: 10.1016/j.ijpharm.2009.07.033.

67. Molavi F., Barzegar-Jalali M., Hamishehkar H. Polyester based polymeric nano and microparticles for pharmaceutical purposes: A review on formulation approaches. Journal of Controlled Release. 2020;320:265–282. DOI: 10.1016/j.jconrel.2020.01.028.

68. Gunatillake P., Adhikari R. Biodegradable synthetic polymers for tissue engineering. European Cells and Materials. 2003;5:1–16 DOI: 10.22203/eCM.v005a01.

69. Bruschi M. L., de Souza Ferreira S. B., Bassi da Silva J. Mucoadhesive and mucus-penetrating polymers for drug delivery. In: Nanotechnology for Oral Drug Delivery. Cambridge: Academic Press; 2020. P. 77–141.

70. Smart J. The basics and underlying mechanisms of mucoadhesion. Advanced Drug Delivery Reviews. 2005;57(11):1556–1568. DOI: 10.1016/j.addr.2005.07.001.

71. Khutoryanskiy V. V. Advances in Mucoadhesion and Mucoadhesive Polymers. Macromolecular Bioscience. 2011;11(6):748–764. DOI: 10.1002/mabi.201000388.

72. Peppas N. A., Buri P. A. Surface, interfacial and molecular aspects of polymer bioadhesion on soft tissues. Journal of Controlled Release. 1985;2:257–275. DOI: 10.1016/0168-3659(85)90050-1.

73. Zhao D., Yu S., Sun B., Gao Sh., Guo S., Zhao K. Biomedical Applications of Chitosan and Its Derivative Nanoparticles. Polymers. 2018;10(4):462. DOI: 10.3390/polym10040462.

74. Sahin A., Yoyen-Ermis D., Caban-Toktas S., Horzum U., Aktas Y., Couvreur P., Esendagli G., Capan Y. Evaluation of brain-targeted chitosan nanoparticles through blood–brain barrier cerebral microvessel endothelial cells. Journal of Microencapsulation. 2017;34(7):659–666. DOI: 10.1080/02652048.2017.1375039.

75. Raj R., Wairkar S., Sridhar V., Gaud R. Pramipexole dihydrochloride loaded chitosan nanoparticles for nose to brain delivery: Development, characterization and in vivo anti-Parkinson activity. International Journal of Biological Macromolecules. 2018;109:27–35. DOI: 10.1016/j.ijbiomac.2017.12.056.

76. Rukmangathen R., Yallamalli I. M., Yalavarthi P. R. Formulation and biopharmaceutical evaluation of risperidoneloaded chitosan nanoparticles for intranasal delivery. Drug Development and Industrial Pharmacy. 2019;45:1342–1350. DOI: 10.1080/03639045.2019.1619759.

77. Keely S., Rullay A., Wilson C., Carmichael A., Carrington S., Corfield A., Haddleton D. M., Brayden D. R. In Vitro and ex Vivo Intestinal Tissue Models to Measure Mucoadhesion of Poly (Methacrylate) and N-Trimethylated Chitosan Polymers. Pharmaceutical Research. 2005;22:38–39. DOI: 10.1007/s11095-004-9007-1.

78. Patel M. M., Smart J. D., Nevell T. G., Ewen R. J., Eaton P. J., Tsibouklis J. Mucin/Poly(acrylic acid) Interactions: A Spectroscopic Investigation of Mucoadhesion. Biomacromolecules. 2003;4:1184–1190. DOI: 10.1021/bm034028p.

79. Porfiryeva N. N., Semina I. I., Salakhov I. A., Moustafine R. I., Khutoryanskiy V. V. Mucoadhesive and mucus-penetrating interpolyelectrolyte complexes for nose-to-brain drug delivery. Nanomedicine: Nanotechnology, Biology and Medicine. 2021;37:102432. DOI: 10.1016/j.nano.2021.102432.

80. Brannigan R. P., Khutoryanskiy V. V. Progress and Current Trends in the Synthesis of Novel Polymers with Enhanced Mucoadhesive Properties. Macromolecular Bioscience. 2019;19(10):1900194. DOI: 10.1002/mabi.201900194.

81. Bernkop-Schnürch A. Thiomers: A new generation of mucoadhesive polymers. Advanced Drug Delivery Reviews. 2005;57:1569–1582. DOI: 10.1016/j.addr.2005.07.002.

82. Leitner V. M., Guggi D., Bernkop‐Schnürch A. Thiomers in noninvasive polypeptide delivery: In vitro and in vivo characterization of a polycarbophil‐cysteine/glutathione gel formulation for human growth hormone. Journal of Pharmaceutical Sciences. 2004;93(7):1682–1691. DOI: 10.1002/jps.20069.

83. Porfiryeva N. N., Nasibullin S. F., Abdullina S. G., Tukhbatullina I. K., Moustafine R. I., Khutoryanskiy V. V. Acrylated Eudragit® E PO as a novel polymeric excipient with enhanced mucoadhesive properties for application in nasal drug delivery. International Journal of Pharmaceutics. 2019;562:241–248. DOI: 10.1016/j.ijpharm.2019.03.027.

84. Tonglairoum P., Brannigan R. P., Opanasopit P., Khutoryanskiy V. V. Maleimide-bearing nanogels as novel mucoadhesive materials for drug delivery. Journal of Materials Chemistry B. 2016;4(40):6581– 6587. DOI: 10.1039/C6TB02124G.

85. Kaldybekov D. B., Tonglairoum P., Opanasopit P., Khutoryanskiy V. V. Mucoadhesive maleimide-functionalised liposomes for drug delivery to urinary bladder. European Journal of Pharmaceu-tical Sciences. 2018;111:83–90. DOI: 10.1016/j.ejps.2017.09.039.

86. Kaldybekov D. B., Filippov S. K., Radulescu A., Khutoryanskiy V. V. Maleimide-functionalised PLGA-PEG nanoparticles as mucoadhesive carriers for intravesical drug delivery. European Journal of Pharmaceutics and Biopharmaceutics. 2019;143:24–34. DOI: 10.1016/j.ejpb.2019.08.007.

87. Mainardes R. M., Khalil N. M., Gremião M. P. D. Intranasal delivery of zidovudine by PLA and PLA–PEG blend nanoparticles. International Journal of Pharmaceutics. 2010;395:266–271. DOI: 10.1016/j.ijpharm.2010.05.020.

88. Guerra-Crespo M., Sistos A., Gleason D., Fallon J. H . Intranasal Administration of PEGylated Transforming Growth Factor-α Improves Behavioral Deficits in a Chronic Stroke Model. Journal of Stroke and Cerebrovascular Diseases. 2010;19:3–9. DOI: 10.1016/j.jstrokecerebrovasdis.2009.09.005.

89. Khutoryanskiy V. V. Beyond PEGylation: Alternative surface-modification of nanoparticles with mucusinert biomaterials. Advanced Drug Delivery Reviews. 2018;124:140–149. DOI: 10.1016/j.addr.2017.07.015.

90. Matsuyama T., Morita T., Horikiri Y., Yamahara H., Yoshino H. Enhancement of nasal absorption of large molecular weight compounds by combination of mucolytic agent and nonionic surfactant. Journal of Controlled Release. 2006;110(2):347–352. DOI: 10.1016/j.jconrel.2005.09.047.

91. Agrawal M., Saraf Sh., Saraf S., Dubey S. K., Puri A., Gupta U., Kesharwani P., Ravichandiran V., Kumar P., Naidu V. G. M., Murty U. S., Ajazuddin, Alexander A. Stimuli-responsive In situ gelling system for nose-to-brain drug delivery. Journal of Controlled Release. 2020;327:235–265. DOI: 10.1016/j.jconrel.2020.07.044.

92. Karavasili C., Fatouros D. G. Smart materials: in situ gelforming systems for nasal delivery. Drug Discovery Today. 2016;21(1):157–166. DOI: 10.1016/j.drudis.2015.10.016.

93. Attwood D., Collett J., Tait C. The micellar properties of the poly(oxyethylene) – poly(oxypropylene) copolymer Pluronic F127 in water and electrolyte solution. International Journal of Phar-maceutics. 1985;26:25–33. DOI: 10.1016/0378-5173(85)90197-8.

94. Naik A., Nair H. Formulation and Evaluation of Thermosensitive Biogels for Nose to Brain Delivery of Doxepin. BioMed Research International. 2014;2014:847547. DOI: 10.1155/2014/847547.

95. Singh R. M., Kumar A., Pathak K. Mucoadhesive in situ nasal gelling drug delivery systems for modulated drug delivery. Expert Opinion on Drug Delivery. 2013;10:115–130. DOI: 10.1517/17425247.2013.746659.

96. Gabal Y. M., Kamel A. O., Sammour O. A., Elshafeey A. H. Effect of surface charge on the brain delivery of nanostructured lipid carriers in situ gels via the nasal route. International Journal of Pharma-ceutics. 2014;473(1–2):442–457. DOI: 10.1016/j.ijpharm.2014.07.025.

97. Cao S., Zhang Q., Jiang X. Preparation of ion-activated in situ gel systems of scopolamine hydrobromide and evaluation of its antimotion sickness efficacy. Acta Pharmacologica Sinica. 2007;28(4):584–590. DOI: 10.1111/j.1745-7254.2007.00540.x.

98. Mathure D., Madan J. R., Gujar K. N., Tupsamundre A., Ranpise H. A., Dua K. Formulation and Evaluation of Niosomal in situ Nasal Gel of a Serotonin Receptor Agonist, Buspirone Hydrochloride for the Brain Delivery via Intranasal Route. Pharmaceutical Nanotechnology. 2018;6(1):69–78. DOI: 10.2174/2211738506666180130105919.

99. Rathnam G., Narayanan N., Ilavarasan R. Carbopol-Based Gels for Nasal Delivery of Progesterone. AAPS PharmSciTech. 2008;9(4):1078–1082. DOI: 10.1208/s12249-008-9144-7.

100. Cho H.-J., Balakrishnan P., Park E.-K., Song K.-W., Hong S.-S., Jang T.-Y., Kim K.-S., Chung S.-J., Shim C.-K., Kim D.-D. Poloxamer/Cyclodextrin/Chitosan-Based Thermoreversible Gel for Intranasal Delivery of Fexofenadine Hydrochloride. Journal of Pharmaceutical Sciences. 2011;100(2):681–691. DOI: 10.1002/jps.22314.