INVESTIGATION OF LEVOMILNACIPRAN NANOSTRUCTURED LIPID CARRIERS FOR CNS DRUG DELIVERY THROUGH INTRANASAL ADMINISTRATION USING RAT MODEL

PARTHIBAN R.; MOTHILAL M.

doi:10.22159/ijap.2025v17i5.54529

Authors

PARTHIBAN R. Department of Pharmaceutics, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu-603203, India. Department of Pharmaceutics, Surya School of Pharmacy, Surya Group of Institutions, Surya Nagar, Vikiravandi, Villupuram Tamil Nadu-603203, India https://orcid.org/0000-0001-5801-8084
MOTHILAL M. Department of Pharmaceutics, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu-603203, India https://orcid.org/0000-0003-0451-2890

DOI:

https://doi.org/10.22159/ijap.2025v17i5.54529

Keywords:

Depression, Levomilnacipran, Nanostructured lipid carrier, Design of experiment, Nasal delivery

Abstract

Objective: This study aims to enhance the pharmacokinetics and pharmacodynamics of levomilnacipran by developing a nanostructured lipid carrier for nasal delivery, bypassing the blood-brain barrier via olfactory and trigeminal pathways to improve drug availability in treating depression.

Methods: The solvent diffusion approach was used to create levomilnacipran nanostructured lipid carriers (LEV-NLC), which was then tuned for different physicochemical properties. The rat model was used to assess the antidepressant effects of optimised levomilnacipran, in conjunction with biochemical assessment of brain monoamines. In addition, this estimated various pharmacokinetic parameters by measuring levomilnacipran levels in brain and blood plasma at different time intervals.

Results: The optimized LEV-NLC showed a particle size of 121 nm, zeta potential of-25 mV, and entrapment efficiency of 88%. Transmission electron microscopy (TEM) analysis revealed spherical nanoparticles with uniform morphology. In vitro release studies demonstrated sustained drug release, with cumulative LEV release of 77.21±3.87% at pH 7.4 and 76.32±3.54% at pH 6.0 over 24 h. Pharmacokinetic analysis showed enhanced bioavailability for LEV-NLC (62%) compared to LEV solution (28%), based on plasma AUC values. In behavioural studies, LEV-NLC significantly reduced immobility (by 101 counts), and increased swimming time (by 128 s), climbing time (by 50 s), and locomotor activity (by 193 counts), indicating antidepressant-like effects. Neurochemical analysis revealed significantly increased serotonin (P<0.01) and noradrenaline (P<0.05) levels in the LEV-NLC group, while dopamine levels showed a non-significant increase (P>0.05).

Conclusion: The pharmacokinetic profile of levomilnacipran in the brain and the brain/blood ratio at various time points were both enhanced by the nose-to-brain delivery of the NLC. Therefore, the intranasal administration of levomilnacipran NLC may hold promise as a treatment for depression.

References

1. Kircanski K, Lieberman MD, Craske MG. Feelings into words: contributions of language to exposure therapy. Psychol Sci. 2012 Oct;23(10):1086-91. doi: 10.1177/0956797612443830, PMID 22902568.

2. Ravikumar L, Velmurugan R, Vidiyala N, Sunkishala P, Teriveedhi VK. Nanotechnology-driven therapeutics for liver cancer: clinical applications and pharmaceutical insights. Asian J Pharm Clin Res. 2025 Feb 7;18(2):8-26. doi: 10.22159/ajpcr.2025v18i2.53429.

3. Janadri S, Dadmi S. Mudagal Mp, Sharma Ur, Vada S, Haribabu T. Alzheimer’s disease: comprehensive insights into risk factors, biomarkers and advanced treatment approaches. Int J Curr Pharm Res. 2025 Jan 15;17(1):1-10.

4. Lenox RH, Frazer A, Lenox RH, Frazer A. Mechanism of action of antidepressants and mood stabilizers. In: Davis KL. Charney D, Coyle JT, Nemeroff C, editors, Neuropsychopharmacology: The Fifth Generation Of Progress. Philadelphia: Lippincott Williams & Wilkins; 2010. p. 1139-63.

5. Marcus M, Yasamy MT, Van Ommeren MV, Chisholm D, Saxena S. Depression: A Global Public Health Concern; 2012. doi: 10.1037/e517532013-004.

6. Kessler RC, Aguilar Gaxiola S, Alonso J, Chatterji S, Lee S, Ormel J. The global burden of mental disorders: an update from the WHO World Mental Health (WMH) surveys. Epidemiol Psichiatr Soc. 2009;18(1):23-33. doi: 10.1017/s1121189x00001421, PMID 19378696.

7. Nutt DJ. Relationship of neurotransmitters to the symptoms of major depressive disorder. J Clin Psychiatry. 2008;69 Suppl E1:4-7. PMID 18494537.

8. Kilts CD. Potential new drug delivery systems for antidepres-sants: an overview. J Clin Psychiatry. 2003;64 Suppl 18:31-3. PMID 14700453.

9. Kumar M, Misra A, Babbar AK, Mishra AK, Mishra P, Pathak K. Intranasal nanoemulsion-based brain targeting drug delivery system of risperidone. Int J Pharm. 2008 Jun;358(1-2):285-91. doi: 10.1016/j.ijpharm.2008.03.029, PMID 18455333.

10. Al Ghananeem AM, Saeed H, Florence R, Yokel RA, Malkawi AH. Intranasal drug delivery of didanosine-loaded chitosan nanoparticles for brain targeting; an attractive route against infections caused by aids viruses. J Drug Target. 2010 Jun;18(5):381-8. doi: 10.3109/10611860903483396, PMID 20001275.

11. Md S, Khan RA, Mustafa G, Chuttani K, Baboota S, Sahni JK. Bro-mocriptine-loaded chitosan nanoparticles intended for direct nose to brain delivery: pharmacodynamic pharmacokinetic and scintigraphy study in mice model. Eur J Pharm Sci. 2013 Feb;48(3):393-405. doi: 10.1016/j.ejps.2012.12.007, PMID 23266466.

12. Ramalingam P, Dutta G, Mohan M, Sugumaran A. Solid lipid nanoparticle a complete tool for brain-targeted drug delivery. Curr Issues Pharm Med Sci. 2025 Mar 31;38(1):11-21. doi: 10.12923/cipms-2025-0002.

13. Parthiban R, MM, Bhupathyraaj M, Sridhar SB, Shareef J, Thomas S. An overview of various approaches for brain-targeted drug delivery system. Int J Nutr Pharmacol Neurol Dis. 2024 Jan;14(1):1-8. doi: 10.4103/ijnpnd.ijnpnd_72_23.

14. Lee D, Minko T. Nanotherapeutics for nose-to-brain drug deliv-ery: an approach to bypass the blood-brain barrier. Pharmaceutics. 2021 Nov 30;13(12):2049. doi: 10.3390/pharmaceutics13122049, PMID 34959331.

15. Mann JJ. The medical management of depression. N Engl J Med. 2005 Oct 27;353(17):1819-34. doi: 10.1056/NEJMra050730, PMID 16251538.

16. Perry R, Cassagnol M. Desvenlafaxine: a new serotonin norepi-nephrine reuptake inhibitor for the treatment of adults with major depressive disorder. Clin Ther. 2009 Jan;31(1):1374-404. doi: 10.1016/j.clinthera.2009.07.012, PMID 19698900.

17. Pawar D, Goyal AK, Mangal S, Mishra N, Vaidya B, Tiwari S. Evaluation of mucoadhesive PLGA microparticles for nasal im-munization. AAPS J. 2010 Jun;12(2):130-7. doi: 10.1208/s12248-009-9169-1, PMID 20077052.

18. Huang Q, Chen Y, Zhang W, Xia X, Li H, Qin M. Nanotechnology for enhanced nose-to-brain drug delivery in treating neurologi-cal diseases. J Control Release. 2024 Feb;366:519-34. doi: 10.1016/j.jconrel.2023.12.054, PMID 38182059.

19. Velmurugan R, Selvamuthukumar S. Development and optimization of ifosfamide nanostructured lipid carriers for oral delivery using response surface methodology. Appl Nanosci. 2016 Feb;6(2):159-73. doi: 10.1007/s13204-015-0434-6.

20. Porsolt RD, Bertin A, Jalfre M. Behavioural despair in rats and mice: strain differences and the effects of imipramine. Eur J Pharmacol. 1978 Oct;51(3):291-4. doi: 10.1016/0014-2999(78)90414-4, PMID 568552.

21. Kitada Y, Miyauchi T, Satoh A, Satoh S. Effects of antidepressants in the rat forced swimming test. Eur J Pharmacol. 1981 Jun;72(2-3):145-52. doi: 10.1016/0014-2999(81)90269-7, PMID 7195816.

22. Paget GE, Barnes JM. Toxicity tests. In: Evaluation of drug activities. Elsevier; 1964. p. 135-66. doi: 10.1016/B978-1-4832-2845-7.50012-8.

23. Costa E, Garattini S, Valzelli L. Interactions between reserpine chlorpromazine and imipramine. Experientia. 1960 Oct;16(10):461-3. doi: 10.1007/BF02171155, PMID 13695781.

24. Schlumpf M, Lichtensteiger W, Langemann H, Waser PG, Hefti F. A fluorometric micromethod for the simultaneous determina-tion of serotonin noradrenaline and dopamine in milligram amounts of brain tissue. Biochem Pharmacol. 1974 Sep;23(17):2437-46. doi: 10.1016/0006-2952(74)90235-4, PMID 4429570.

25. Md S, Khan RA, Mustafa G, Chuttani K, Baboota S, Sahni JK. Bro-mocriptine-loaded chitosan nanoparticles intended for direct nose-to-brain delivery: pharmacodynamic, pharmacokinetic and scintigraphy study in mice model. Eur J Pharm Sci. 2013 Feb;48(3):393-405. doi: 10.1016/j.ejps.2012.12.007, PMID 23266466.

26. Raut BB, Kolte BL, Deo AA, Bagool MA, Shinde DB. A rapid and sensitive HPLC method for the determination of venlafaxine and O‐Desmethylvenlafaxine in human plasma with UV detection. J Liq Chromatogr Relat Technol. 2003 Apr;26(8):1297-313. doi: 10.1081/JLC-120020112.

27. Lucki I. The forced swimming test as a model for core and com-ponent behavioral effects of antidepressant drugs. Behav Phar-macol. 1997 Nov;8(6-7):523-32. doi: 10.1097/00008877-199711000-00010, PMID 9832966.

28. Berney P. Dose response relationship of recent antidepressants in the short-term treatment of depression. Dial Clin Neurosci. 2005 Sep 30;7(3):249-62. doi: 10.31887/DCNS.2005.7.3/pberney, PMID 16156383.

29. Reneric JP, Bouvard M, Stinus L. In the rat forced swimming test chronic but not subacute administration of dual 5-HT/NA anti-depressant treatments may produce greater effects than selec-tive drugs. Behav Brain Res. 2002 Nov;136(2):521-32. doi: 10.1016/s0166-4328(02)00203-6, PMID 12429415.

30. Reneric JP, Lucki I. Antidepressant behavioral effects by dual inhibition of monoamine reuptake in the rat forced swimming test. Psychopharmacol (Berl). 1998 Mar 11;136(2):190-7. doi: 10.1007/s002130050555, PMID 9551776.

31. Hermann DM, Bassetti CL. Implications of ATP-binding cassette transporters for brain pharmacotherapies. Trends Pharmacol Sci. 2007 Mar;28(3):128-34. doi: 10.1016/j.tips.2007.01.007, PMID 17275929.

32. Alam MI, Baboota S, Ahuja A, Ali M, Ali J, Sahni JK. Intranasal administration of nanostructured lipid carriers containing CNS acting drug: pharmacodynamic studies and estimation in blood and brain. J Psychiatr Res. 2012 Sep;46(9):1133-8. doi: 10.1016/j.jpsychires.2012.05.014, PMID 22749490.

33. Richelson E. Antidepressants and brain neurochemistry. Mayo Clin Proc. 1990 Sep;65(9):1227-36. doi: 10.1016/s0025-6196(12)62747-5, PMID 2169557.

34. Arnsten AF. Stress signalling pathways that impair prefrontal cortex structure and function. Nat Rev Neurosci. 2009 Jun;10(6):410-22. doi: 10.1038/nrn2648, PMID 19455173.

35. Weiss JM, Goodman PA, Losito BG, Corrigan S, Charry JM, Bailey WH. Behavioral depression produced by an uncontrollable stressor: relationship to norepinephrine dopamine and sero-tonin levels in various regions of rat brain. Brain Res Rev. 1981 Oct;3(2):167-205. doi: 10.1016/0165-0173(81)90005-9.

36. Illum L. Transport of drugs from the nasal cavity to the central nervous system. Eur J Pharm Sci. 2000 Jul;11(1):1-18. doi: 10.1016/s0928-0987(00)00087-7, PMID 10913748.

37. Thorne RG, Frey WH. Delivery of neurotrophic factors to the central nervous system: pharmacokinetic considerations. Clin Pharmacokinet. 2001;40(12):907-46. doi: 10.2165/00003088-200140120-00003, PMID 11735609.

38. Artursson P, Lindmark T, Davis SS, Illum L. Effect of chitosan on the permeability of monolayers of intestinal epithelial cells (Caco-2). Pharm Res. 1994;11(9):1358-61. doi: 10.1023/a:1018967116988, PMID 7816770.

39. Pund S, Rasve G, Borade G. Ex vivo permeation characteristics of venlafaxine through sheep nasal mucosa. Eur J Pharm Sci. 2013 Jan;48(1-2):195-201. doi: 10.1016/j.ejps.2012.10.029, PMID 23159662.