In situ Intranasal Delivery Systems: Application Prospects and Main Pharmaceutical Aspects of Development (Review)

Introduction. Intranasal delivery of in situ gel-forming systems is a complex but promising direction. Due to the high cost of developing a new chemical object or genetically engineered modification of biological molecules, pharmaceutical companies are focusing on developing technologies for new delivery systems for existing active pharmaceutical ingredients to improve their effectiveness and bioavailability. In situ systems for intranasal delivery, due to increased viscosity and mucoadhesion to the nasal mucosa, allow overcoming mucociliary clearance and ensuring complete absorption and prolonged release of drugs.

Text. The article discusses the main advantages of intranasal in situ delivery systems shown in preclinical studies, as well as approaches to the technology of obtaining and standardization of these systems. The results of scientific research in this field over the past 15 years are summarized, the most promising polymers for creating thermoreversible and pH-sensitive compositions are identified, and modern methods for evaluating the sol-gel transition in situ are analyzed.

Conclusion. The use of in situ systems for intranasal administration allows providing a high targeting of the delivery of synthetic and biological molecules to the brain. Currently, numerous pharmacokinetic and pharmacodynamic preclinical studies confirm the effectiveness of such systems, as well as their safety. Thermoreversible commercially available and directionally synthesized polymers (poloxamer 407, PLGA, NIPAAm, etc.), as well as chitosan, remain the most popular for the design of in situ delivery systems. In vitro and ex vivo methods with mucosa and artificial nasal fluid are widely used to assess the parameters of in situ gelation, but to increase the reproducibility of the methods and improve the correlation in vitro/in vivo, it is recommended to conduct modeling of the nasal cavity. Developing the technology and methods of screening of intranasal reversible systems will help to get closer to clinical trials and the entry of these delivery systems into the global pharmaceutical market.

1. Demina N. B., Bakhrushina E. O., Bardakov A. I., Krasnyuk I. I. Design of intranasal dosage forms: biopharmaceutical aspects. Far-matsiya = Pharmacy. 2019;68(3):12-17. (In Russ.)

2. Suman J. D., Laube B. L., Lin T.-Ch., Brouet G., Dalby R. Validity of in vitro tests on aqueous spray pumps as surrogates for nasal deposition. Pharm Res. 2002;19(1):1-6. DOI: 10.1023/a:1013643912335.

3. Rohrer J., Lupo N., Bernkop-Schnurch A. Advanced formulations for intranasal delivery of biologics. International Journal of Pharmaceutics. 2018;553(1-2):8-20. DOI: 10.1016/j.ijpharm.2018.10.029.

4. Bariev E. A., Krasnyuk I. I., Anurova M. N., Bakhrushina E. O., Smirnov V. V., Bardakov A. I., Demina N. B., Krasnyuk (Jr.) I. I. Study of the acute toxicity of a new dosage form of naloxone hydrochloride for intranasal administration. Drug Research. 2020;70(1):23-25. DOI: 10.1055/a-0899-4948.

5. Singh R. M. P., Kumar A., Pathak K. Mucoadhesive <I>in situ</I> nasal gelling drug delivery systems for modulated drug delivery. Expert Opinion on Drug Delivery. 2013;10(1):115-130. DOI: 10.1517/17425247.2013.746659.

6. 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.

7. Birmingham A. The topographical anatomy of the spleen, pancreas, duodenum, kidneys, &c: illustrated by a cast of these viscera hardened in situ. J Anat Physiol. 1896;31(1):95-113.

8. De Bethizy J. D., Street J. C. Unique purified hydrated-gelatin diet for feeding dietary fiber to Wistar rats. Lab Anim Sci. 1984;34(1):44-48.

9. Bromberg L. E. Enhanced nasal retention of hydrophobically modified polyelectrolytes. Journal of Pharmacy and Pharmacology. 2010;53(1):109-114. DOI: 10.1211/0022357011775082.

10. Song S.-Ch., Lee S. B., Lee B. H., Ha H.-W., Lee K.-T., Sohn Y. S. Synthesis and antitumor activity of novel thermosensitive platinum(II)-cyclotriphosphazene conjugates. Journal of Controlled Release. 2003;90(3):303-311. DOI: 10.1016/s0168-3659(03)00199-8.

11. Bilensoy E., Rouf M. A., Vural I., Sen M., Hincal A. A. Mucoadhesive, thermosensitive, prolonged-release vaginal gel for clotrimazole: β-cyclodextrin complex. AAPS PharmSciTech. 2006;7(2):E54. DOI: 10.1208/pt070238.

12. Bakhrushina E. O., Nikiforova D. A., Demina N. B. The main aspects of the thermorreversible polycomplexes of poloxamers developing. Zdorov'e i obrazovanie v XXI veke = Health and education in the XXI century. 2018;20(5):103-106. DOI: 10.26787/nydha-2226-7425-2018-20-5-103-106. (In Russ.)

13. Hu K.-L., Mei N., Feng L., Jiang X.-G. Hydrophilic nasal gel of lidocaine hydrochloride. 2nd communication: Improved bioavailability and brain delivery in rats with low ciliotoxicity. Arzneimittelforschung. 2009;59(12):635-640. DOI: 10.1055/s-0031-1296452.

14. Zhang L., Pang L., Zhu S., Ma J., Li R., Liu Y., Zhu L., Zhuang X., Zhi W., Yu X., Du L., Zuo H., Jin Y. Intranasal tetrandrine temperature-sensitive in situ hydrogels for the treatment of microwave-induced brain injury. International Journal of Pharmaceutics. 2020;583:119384. DOI: 10.1016/j.ijpharm.2020.119384.

15. Wang Q.-S., Li K., Gao L.-N., Zhang Y., Lin K.-M., Cui Y.-L. Intranasal delivery of berberine via in situ thermoresponsive hydrogels with non-invasive therapy exhibits better antidepressant-like effects. Biomaterials Science. 2020;8(10):2853-2865. DOI: 10.1039/c9bm02006c.

16. Bachhav S. S., Dighe V., Mali N., Gogtay N. J., Thatte U. M., Devarajan D. V. Nose-to-brain delivery of diazepam from an intranasal aqua-triggered in-situ (ATIS) gelling microemulsion: monitoring brain uptake by microdialysis. European Journal of Drug Metabolism and Pharmacokinetics. 2020;45(6):785-799. DOI: 10.1007/s13318-020-00641-5.

17. Yin P., Li H., Ke Ch., Cao G., Xin X., Hu J., Cai X., Li L., Liu H., Du B. Intranasal delivery of immunotherapeutic nanoformulations for treatment of glioma through in situ activation of immune response. International Journal of Nanomedicine. 2020;15:1499-1515. DOI: 10.2147/IJN.S240551.

18. Salem H. F., Kharshoum R. M., Abou-Taleb H. A., Naguib D. M. Nanosized transferosome-based intranasal in situ gel for brain targeting of resveratrol: formulation, optimization, in vitro evaluation, and in vivo pharmacokinetic study. AAPS PharmSciTech. 2019;20(5):181. DOI: 10.1208/s12249-019-1353-8.

19. Wang Q., Wong Ch.-H., Chan H.Y.E., Lee W.-Y., Zuo Zh. Statistical design of experiment (DoE) based development and optimization of DB213 in situ thermosensitive gel for intranasal delivery. International Journal of Pharmaceutics. 2018;539(1-2):50-57. DOI: 10.1016/j.ijpharm.2018.01.032.

20. Sun Y., Li L., Xie H., Wang Y., Gao Sh., Zhang L., Bo F., Yang Sh., Feng A. Primary studies on construction and evaluation of ion-sensitive in situ gel loaded with paeonol-solid lipid nanoparticles for intranasal drug delivery. International Journal of Nanomedicine. 2020;15:3137-3160. DOI: 10.2147/IJN.S247935.

21. Majcher M. J., Babar A., Lofts A., Leung A., Li X., Abu-Hijleh F., Smeets N. M. B., Mishra R. K., Hoare T. In situ-gelling starch nanoparticle (SNP)/O-carboxymethyl chitosan (CMCh) nanoparticle network hydrogels for the intranasal delivery of an antipsychotic peptide. Journal of Controlled Release. 2021;330:738-752. DOI: 10.1016/j.jconrel.2020.12.050.

22. Rajput A., Bariya A., Allam A., Othman S., Butani S. B. In situ nanostructured hydrogel of resveratrol for brain targeting: in vitro-in vivo characterization. Drug Delivery and Translational Research. 2018;8(5):1460-1470. DOI: 10.1007/s13346-018-0540-6.

23. Ball J. P., Springer M. J., Ni Y., Finger-Baker I., Martinez J., Hahn J., Suber J. F., DiMarco A. V., Talton J. D., Cobb R. R. Intranasal delivery of a bivalent norovirus vaccine formulated in an in situ gelling dry powder. PLoS One. 2017;12(5):e0177310. DOI: 10.1371/journal.pone.0177310.

24. Mohamed S., Nasr M., Salama A., Refai H. Novel lipid-polymer hybrid nanoparticles incorporated in thermosensitive in situ gel for intranasal delivery of terbutaline sulphate. Journal of Microencapsulation. 2020;37(8):577-594. DOI: 10.1080/02652048.2020.1826590.

25. 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.

26. Sherje A. P., Londhe V. Development and evaluation of pH-responsive cyclodextrin-based in situ gel of paliperidone for intranasal delivery. AAPS PharmSciTech. 2018;19(1):384-394. DOI: 10.1208/s12249-017-0844-8.

27. Chen Y., Liu Y., Xie J., Zheng Q., Yue P., Chen L., Hu P., Yang M. Nose-to-brain delivery by nanosuspensions-based in situ gel for breviscapine. International Journal of Nanomedicine. 2020;15:10435-10451. DOI: 10.2147/IJN.S265659.

28. Akilo O. D., Kumar P., Choonara Y. E., du Toit L. C., Pradeep P., Modi G., Pillay V. In situ thermo-co-electroresponsive mucogel for controlled release of bioactive agent. International Journal of Pharmaceutics. 2019;559:255-270. DOI: 10.1016/j.ijpharm.2019.01.044.

29. Qian Sh., Wong Y. Ch., Zuo Zh. Development, characterization and application of in situ gel systems for intranasal delivery of tacrine. International Journal of Pharmaceutics. 2014;468(1-2):272-282. DOI: 10.1016/j.ijpharm.2014.04.015.

30. Salatin S., Barar J., Barzegar-Jalali M., Adibkia Kh., Jelvehgari M. Thermosensitive in situ nanocomposite of rivastigmine hydrogen tartrate as an intranasal delivery system: Development, characterization, ex vivo permeation and cellular studies. Colloids and Surfaces B: Biointerfaces. 2017;159:629-638. DOI: 10.1016/j.colsurfb.2017.08.031.

31. Patil R. P., Pawara D. D., Gudewar Ch. S., Tekade A. R. Nanostructured cubosomes in an in situ nasal gel system: an alternative approach for the controlled delivery of donepezil HCl to brain. Journal of Liposome Research. 2019;29(3):264-273. DOI: 10.1080/08982104.2018.1552703.

32. Lee B. H., West B., McLemore R., Pauken Ch., Vernon B. L. In-situ injectable physically and chemically gelling NIPAAm-based copolymer system for embolization. Biomacromolecules. 2006;7(6):2059-2064. DOI: 10.1021/bm060211h.

33. Lee B. H., Vernon B. In situ-gelling, erodible N-isopropylacrylamide copolymers. Macromolecular Bioscience. 2005;5(7):629-635. DOI: 10.1002/mabi.200500029.

34. Lee B. H., Beart H. H., Cheng V., McLemore R., Robb S. A., Cui Zh., Dovigi A., Vernon B. L. In vitro and in vivo demonstration of physically and chemically in situ gelling NIPAAm-based copolymer system. Journal of Biomaterials Science, Polymer Edition. 2013;24(13):1575-1588. DOI: 10.1080/09205063.2013.781939.

35. Li Chen., Li Chun., Liu Zh., Li Q., Yan X., Liu Y., Lu W. Enhancement in bioavailability of ketorolac tromethamine via intranasal in situ hydrogel based on poloxamer 407 and carrageenan. International Journal of Pharmaceutics. 2014;474(1-2):123-133. DOI: 10.1016/j.ijpharm.2014.08.023.

36. Pandey P., Pandey S., Cabot P. J., Wallwork B., Panizza B. J., Parekh H. S. Toxicity evaluation and nasal mucosal tissue deposition of dexamethasone-infused mucoadhesive in situ nasal gelling systems. Saudi Pharmaceutical Journal. 2019;27(7):914-919. DOI: 10.1016/j.jsps.2019.06.005.

37. Ahmad N., Ahmad R., Ahmad F. J., Ahmad W., Alam M. A., Amir M., Ali A. Poloxamer-chitosan-based Naringenin nanoformulation used in brain targeting for the treatment of cerebral ischemia. Saudi Journal of Biological Sciences. 2020;27(1):500-517. DOI: 10.1016/j.sjbs.2019.11.008.

38. Zakir F., Ahmad A., Farooq U., Mirza M. A., Tripathi A., Singh D., Shakeel F., Mohapatra S., Ahmad F. J., Kohli K. Design and development of a commercially viable in situ nanoemulgel for the treatment of postmenopausal osteoporosis. Nanomedicine. 2020;15(12):1167-1187. DOI: 10.2217/nnm-2020-0079.

39. Kharenko E. A., Larionova N. I., Demina N. B. Mucoadhesive drug delivery systems. Khimiko-Farmatsevticheskii Zhurnal = Pharmaceutical Chemistry Journal. 2009;43(4):21-29. (In Russ.)

40. Bakhrushina E., Anurova M., Demina N., Kashperko A., Rastopchina O., Bardakov A., Krasnyuk I. Comparative study of the mucoadhesive properties of polymers for pharmaceutical use. Open Access Macedonian Journal of Medical Sciences. 2020; 8(A):639-645. DOI: 10.3889/oamjms.2020.4930.

41. Paul A., Fathima K. M., Nair S. C. Intra nasal in situ gelling system of lamotrigine using ion activated mucoadhesive polymer. The Open Medicinal Chemistry Journal. 2017;11 (1 ):222-244. DOI: 10.2174/1874104501711010222.

42. Mahajan, H. S. Gattani S. In situ gels of Metoclopramide Hydrochloride for intranasal delivery: In vitro evaluation and in vivo pharmacokinetic study in rabbits. Drug Delivery. 2010;17(1):19-27. DOI: 10.3109/10717540903447194.

43. Kulkarni J. A., Avachat A. M. Pharmacodynamic and pharmacokinetic investigation of cyclodextrin-mediated asenapine maleate in situ nasal gel for improved bioavailability. Drug Development and Industrial Pharmacy. 2017;43(2):234-245. DOI: 10.1080/03639045.2016.1236808.

44. Gholizadeh H., Cheng Sh., Pozzoli M., Messerotti E., Traini D., Young P., Kourmatzis A., Ong H. X. Smart thermosensitive chitosan hydrogel for nasal delivery of ibuprofen to treat neurological disorders. Expert Opinion on Drug Delivery. 2019;16(4):453-466. DOI: 10.1080/17425247.2019.1597051.

45. Uppuluri Ch. T., Ravi P. R., Dalvi A. V., Shaikh Sh. Sh., Kale S. R. Piribedil loaded thermo-responsive nasal in situ gelling system for enhanced delivery to the brain: formulation optimization, physical characterization, and in vitro and in vivo evaluation. Drug Delivery and Translational Research. 2021;11(3):909-926. DOI: 10.1007/s13346-020-00800-w.

46. Le Guellec S., Ehrmann S., Vecellio L. In vitro - in vivo correlation of intranasal drug deposition. Advanced Drug Delivery Reviews. 2021;170:340-352. DOI: 10.1016/j.addr.2020.09.002.

47. Keustermans W., Huysmans T., Danckaers F., Zarowski A., Schmelzer B., Sijbers J., Dirckx J. J. J. High quality statistical shape modelling of the human nasal cavity and applications. Royal Society Open Science. 2018;5(12):181558. DOI: 10.1098/rsos.181558.

48. Moller W., Celik G., Feng Sh., Bartenstein P., Meyer G., Eickelberg O., Schmid O., Tatkov S. Nasal high flow clears anatomical dead space in upper airway models. Journal of Applied Physiology. 2015;118(12):1525-1532. DOI: 10.1152/japplphysiol.00934.2014.

49. Liu Y., Johnson M. R., Matida E. A., Kherani S., Marsan J. Creation of a standardized geometry of the human nasal cavity. Journal of Applied Physiology. 2009;106(3):784-795. DOI: 10.1152/japplphysiol.90376.2008.

50. Corey J. P., Gungor A., Nelson R., Fredberg J., Lai V. A Comparison of the nasal cross-sectional areas and volumes obtained with acoustic rhinometry and magnetic resonance imaging. Otolaryngology-Head and Neck Surgery. 1997;117(4):349-354. DOI: 10.1016/S0194-5998(97)70125-6.

51. Cheng K.-H., Cheng Y.-S., Yeh H.-Ch., Guilmette R. A., Simpson S. Q., Yang Y.-H., Swift D. L. In vivo measurements of nasal airway dimensions and ultrafine aerosol deposition in the human nasal and oral airways. Journal of Aerosol Science. 1996;27(5):785-801. DOI: 10.1016/0021-8502(96)00029-8.

52. Calmet H., Inthavong K., Eguzkitza B., Lehmkuhl O., Houzeaux G., Vazquez M. Nasal sprayed particle deposition in a human nasal cavity under different inhalation conditions. PLoS One. 2019;14(9):e0221330. DOI: 10.1371/journal.pone.0221330.

53. Chen J. Z., Kiaee M., Martin A. R., Finlay W. H. In vitro assessment of an idealized nose for nasal spray testing: Comparison with regional deposition in realistic nasal replicas. International Journal of Pharmaceutics. 2020;582:119341. DOI: 10.1016/j.ijpharm.2020.119341.

54. Kundoor V., Dalby R. N. Assessment of nasal spray deposition pattern in a silicone human nose model using a color-based method. Pharmaceutical Research. 2010;27(1):30-36. DOI: 10.1007/s11095-009-0002-4.

55. Warnken Z. N., Smyth H. D. C., Davis D. A., Weitman S., Kuhn J. G., Williams R. O. Personalized medicine in nasal delivery: The use of patient-specific administration parameters to improve nasal drug targeting using 3D-printed nasal replica casts. Molecular Pharmaceutics. 2018;15(4):1392-1402. DOI: 10.1021/acs.molpharmaceut.7b00702.